Method for the Treatment of Myeloproliferative Diseases Using(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2- Methylsulfonylethyl]-4- Acetylaminoisoindoline-1,3- Dione

ABSTRACT

Methods of treating, preventing and/or managing a myeloproliferative disease are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent, and/or the transplantation of blood or cells. Particular second active agent is capable of suppressing the overproduction of hematopoietic stem cells or ameliorating one or more of the symptoms of MPD. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

1. FIELD OF THE INVENTION

This invention relates to methods of treating, preventing and/ormanaging myeloproliferative diseases and related syndromes whichcomprise the administration of selective cytokine inhibitory drugs aloneor in combination with other therapies.

2. BACKGROUND OF THE INVENTION

2.1 Pathobiology of MPD

Myeloproliferative disease (MPD) refers to a group of disorderscharacterized by clonal abnormalities of the hematopoietic stem cell.See e.g., Current Medical Diagnosis & Treatment, pp. 499 (37^(th) ed.,Tierney et al. ed, Appleton & Lange, 1998). Since the stem cell givesrise to myeloid, erythroid, and platelet cells, qualitative andquantitative changes can be seen in all these cell lines. Id.

MPD is further subdivided on the basis of the predominantlyproliferating myeloid cell type. Erythrocyte excess is classified as“polycythemia rubra vera PRV)” or “polycythemia vera,” platelet excessas “primary (or essential) thromobocythemia (PT),” and granulocyteexcess as “chronic myelogenous leukemia (CML).” A fourth subcategory ofMPD is “agnogenic myeloid metaplasia (AMM),” which is characterized bybone marrow fibrosis and extramedullary hematopoiesis. Cecil Textbook ofMedicine, pp. 922 (20^(th) ed., Bennett and Plum ed., W.B. SaundersCompany, 1996). These disorders are grouped together because the diseasemay evolve from one form into another and because hybrid disorders arecommonly seen. Tierney et al, supra, at pp. 499. All of themyeloproliferative disorders may progress to acute leukemia naturally oras a consequence of mutagenic treatment. Id.

Most patients with PRV present symptoms related to expanded blood volumeand increased blood viscosity. Id. at pp. 500. Common complaints includeheadache, dizziness, tinnitus, blurred vision, and fatigue. Id. Thespleen is palpably enlarged in 75% of cases, but splenomegaly is nearlyalways present when imaged. Id. Thrombosis is the most commoncomplication of PRV and the major cause of morbidity and death in thisdisorder. Thrombosis appears to be related to increased blood viscosityand abnormal platelet function. Id. Sixty percent of patients with PRVare male, and the median age at presentation is 60. It rarely occurs inadults under age 40. Id.

Thrombosis is also a common complication in patients suffering from PT.Cecil Textbook of Medicine, pp. 922 (20^(th) ed., Bennett and Plum ed.,W.B. Saunders Company, 1996). A platelet count ≧6×10⁵ per microliter hasbeen set to diagnose PT. Tefferi et al., Mayo Clin Proc 69:651 (1994).Most patients are asymptomatic when PT is diagnosed, usually throughincidental discovery of increased peripheral blood platelet count.Bennett and Plum, supra, at pp. 922. Approximately one quarter, however,have either thrombotic or hemorrhagic events. Id. PT rarely transformsinto acute leukemia or AMM, and most patients have a normal lifeexpectancy. Id. at pp. 923. However, at least one third of patients withPT eventually undergo major thrombohemorrhage complications. Id.

In CML patients, normal bone marrow function is typically retainedduring the early stage. Tierney et al, supra, at pp. 503. The diseaseusually remains stable for years and then transforms to a more overtlymalignant disease. Id. CML eventually progresses to blast crisis, whichis indistinguishable from acute leukemia. Id. CML is typically adisorder of middle age (median age at presentation is 42 years). Id.Acceleration of the disease is often associated with fever in theabsence of infection, bone pain, and splenomegaly. Id. One of thehallmarks of CML laboratory findings is an elevated white blood count:the median white blood count at diagnosis is 150,000/μL. Id. Mediansurvival of CML is 3-4 years. Id. at pp. 505. Once the disease hasprogressed to the accelerated or blast phase, survival is typicallymeasured in months. Id.

AMM is characterized by fibrosis of the bone marrow, splenomegaly, and aleukoerythroblastic peripheral blood picture with teardroppoikilocytosis. Tierney et al, supra, at pp. 502. AMM develops in adultsover age 50 and is usually insidious in onset. Id. Later in the courseof the disease, bone marrow failure takes place as the marrow becomesprogressively more fibrotic. Id. Anemia becomes severe. Id. Painfulepisodes of splenic infarction may occur. Severe bone pain and liverfailure also occur in the late stage of AMM. Id. The median survivalfrom time of diagnosis is approximately 5 years. Id. at pp. 503.

The precise cause of MPD is not clear. Current data suggest some growthfactors are involved. For instance, in both PRV and PT, in contrast tonormal erythroid progenitor cells, polycythemia vera erythroidprogenitor cells can grow in vitro in the absence of erythropoietin dueto hypersensitivity to insulin like growth factor I. Harrison'sPrinciples of Internal Medicine, pp. 701 (15^(th) ed., Braunwald et al.ed., McGraw-Hill, 2001). In AMM, the overproduction of type III collagenhas been attributed to platelet-derived growth factor or transforminggrowth factor β (TGF-β). Id. at pp. 703; see also, Martyr_(—) , LeukLymphonia 6:1 (1991).

In some MPD forms, specific chromosomal changes are seen. For instance,nonrandom chromosome abnormalities, such as 20q-, trisomy 8 or 9 havebeen documented in a small percentage of untreated PRV patients, and20q-, 13q-, trisomy 1q are common in AMM patient. Harrison's Principlesof Internal Medicine, pp. 701-3 (15^(th) ed., Braunwald et al. ed.,McGraw-Hill, 2001). Philadelphia chromosome is present in the bonemarrow cells of more than 90% of patients with typical CML and somepatients with PRV. See e.g., Kurzrock et al., N Engl J Med 319:990(1988). The Philadelphia chromosome results from a balancedtranslocation of material between the long arms of chromosomes 9 and 22.The break, which occurs at band q34 of the long arm of chromosome 9,allows translocation of the cellular oncogene C-ABL to a position onchromosome 22 called the breakpoint cluster region (bcr). The appositionof these two genetic sequences produces a new hybrid gene (BCR/ABL),which codes for a novel protein of molecular weight 210,000 kD P210).The P210 protein, a tyrosine kinase, may play a role in triggering theuncontrolled proliferation of CML cells. See e.g., Daley et al., Science247:824 (1990).

The risk of the CML type of MPD also increases upon exposure to ionizingradiation. Survivors of the atomic bomb explosions in Japan in 1945 havehad an increased incidence of CML, with a peak occurring 5 to 12 yearsafter exposure and seeming to be dose related. Cecil Textbook ofMedicine, pp. 925-926 (20^(th) ed., Bennett and Plum ed., W.B. SaundersCompany, 1996). Radiation treatment of ankylosing spondylitis andcervical cancer has increased the incidence of CML. Id

The incidence of MPD varies depending on the form of the disease. CMLconstitutes one fifth of all cases of Leukemia in the United States. Id.at pp. 920. Approximately 4300 new cases of CML are diagnosed in theUnited States every year, accounting for more than half of MPD cases.(eMedicine website, myeloproliferative disease). PRV is diagnosed in5-17 persons per 1,000,000 per year. Id. True incidences of PT and AMMare not known because epidemiological studies on these disorders areinadequate. Id. Internationally, CML appears to affect all races withapproximately equal frequency. PRV is reportedly lower in Japan, i.e., 2person per 1,000,000 per year. Id.

2.2 MPD Treatment

The treatment of choice for PRV is phlebotomy. Current Medical Diagnosis& Treatment, pp. 501 (37^(th) ed., Tierney et al. ed, Appleton & Lange,1998). One unit of blood (approximately 500 mL) is removed weekly untilthe hematocrit is less than 45%. Id. Because repeated phlebotomyproduces iron deficiency, the requirement for phlebotomy has to begradually decreased. Id. It is important to avoid medicinal ironsupplementation, as this can thwart the goals of a phlebotomy program.Id.

In more severe cases of PRV, myelosuppressive therapy is used. Id. Oneof the widely used myelosuppressive agents is hydroxyurea. Id.Hydroxyurea is an oral agent that inhibits ribonucleotide reductase.Bennett and Plum, supra, at pp. 924. The usual dose is 500-1500 mg/dorally, adjusted to keep platelets <500,000/μL without reducing theneurophil count to <2000/μL. Tierney et al., supra, at pp. 501. Sideeffects of hydroxyurea include mild gastrointestinal complaints,reversible neutropenia, and mucocutaneous lesions. Bennett and Plum,supra, at pp. 924. Busulfan may also be used in a dose of 4-6 mg/d for4-8 weeks. Tierney et al., supra, at pp. 501. Alpha interferon has beenshown to have some ability to control the disease. The usual dose is 2-5million units subcutaneously three times weekly. Id. Anagrelide has alsobeen approved for use in treatment of thrombocytosis. Id. Some of themyelosuppressive agents, such as alkylating agents and radiophosphorus(³²P), have been shown to increase the risk of conversion of PRV toacute leukemia. Id. Using myelosuppressive agents for long period maycause prolonged severe myelosuppression.

Most authorities agree that treatment of PT should be aimed atdecreasing the level of platelets in patients with a history ofthrombosis as well as those with cardiovascular risk factors. Bennettand Plum, supra, at pp. 923. However, the benefit of specific therapyhas not been established, and there is concern about the leukemogenicpotential of the available therapeutic agents. Id. When treatment isdecided upon, the initial drugs are hydroxyurea or anagrelide. Id. atpp. 924. Anagrelide is an oral agent that may involve inhibition ofmegakaryocyte maturation. Id. The starting dose is 0.5 mg given fourtimes a day. Id. It is relatively contraindicated in elderly patientswith heart disease. Id. Alpha interferon can also be used in thetreatment of PT. Id.

Currently, there is no specific treatment for AMM. Tierney et al.,supra, at pp. 502. The management of AMM is directed to symptoms. Anemicpatients are supported with red blood cells in transfusion. Id.Androgens such as oxymetholone, 200 mg orally daily, or testosteronehelp reduce the transfusion requirement in one third of cases but arepoorly tolerated by women. Id. Splenectomy is indicated for splenicenlargement that causes recurrent painful episodes, severethrombocytopenia, or an unacceptable high red blood cell transfusionrequirement. Id. Alpha interferon (2-5 million units subcutaneouslythree times weekly) leads to improvement in some cases. Id.

Immediate treatment of CML is not necessary unless the white blood cell(WBC) count exceeds 200,000 per microliter or there is evidence ofleukostasis (priapism, venous thrombosis, confusion, or dyspnes) orthere is splenic infarction. Id. at pp. 504. Standard therapy of CMLconsists of administration of hydroxyurea. Id. Hydroxyurea must be givenwithout interruption, since the white blood count will rise within daysafter discontinuing the medication. Id. Recombinant alpha interferon haslargely replaced hydroxyurea as the initial treatment of choice and canprolong both the duration of the chronic phase and overall survival. Id.Interferon, unlike other palliative agents, can suppress thePhiladelphia chromosome and to allow cytogenetically normal cells toappear. Id.

Although the response to myelosuppressive therapy of the chronic phaseof CML is gratifying, the treatment is only palliative, and the diseaseis invariably fatal. Id. The only available curative therapy isallogenic bone marrow transplantation. Id. This treatment is availablefor adults under age 60 who have HLA-matched siblings. Id. Approximately60% of adults have long term disease-free survival following bone marrowtransplantation. Id. However, such treatment is limited by the donorsource and the age of the patient. For CML patients who relapse aftertransplantation, immunologic therapy with infusion of T lymphocytes fromthe bone marrow donor may produce long-lasting remissions. Id. at pp504-5. Blast crisis of CML can be treated with daunorubicin,cincristine, and prednisone (used in treatment of acute lymphoblasticleukemia), although the remission is usually short-lived. Id. at pp.505.

Persistent efforts have been made to find new ways to treat CML. Forinstance, the synthetic inhibitor of the BCR/ABL kinase, ST1571, inducesselective inhibition in the growth of t(9;22)-bearing tumor cells invitro and some responses in patients. See, e.g., Buchdunger et al.,Proc. Natl. Acad. Sci. USA 92:2558-2562 (1995); and Buchdunger et al.,Cancer Res., 56:100-104 (1996). See also Harrison's Principles ofInternal Medicine, pp. 714 (15^(th) ed., Braunwald et al. ed.,McGraw-Hill, 2001). Inhibition of RAS with a farnesyl transferaseinhibitor that blocks its insertion into the membrane may have antitumoractivity in CML based on early clinical trials. See Braunwald et al.,supra, at 714. Preclinical efforts to use BCR/ABL peptides as a tumorvaccine appear promising. Id. The use of BCR/ABL antisenseoligonucleotides to purge residual leukemic cells from autologoushematopoietic progenitors before reinfusion, as will as approaches toinduce GVL (graft-versus-leukemia) in the setting of minimal residualdisease (remission stage wherein the leukemia cell counts are below whatcan be detected by the traditional technology, usually ≦10¹⁰ malignantcells) without inducing GVHD (graft-versus-host disease), are underway.Id.

Since most therapies used in the treatment of MPD are targeted only atsymptoms, and most agents used have serious side effects, with thedanger of causing severe myelosuppression or converting the disorder toacute leukemia, there is a great need to find new treatments of MPD thateither target the underlying cause of the disorder or improve theeffectiveness and safety of the current treatments.

2.3 Selective Cytokine Inhibitory Drugs

Compounds referred to as SelCIDs™ (Celgene Corporation) or SelectiveCytokine Inhibitory Drugs have been synthesized and tested. Thesecompounds potently inhibit TNF-α production, but exhibit modestinhibitory effects on LPS induced IL1β and IL12, and do not inhibit IL6even at high drug concentrations. In addition, SelCIDs™ tend to producea modest IL10 stimulation. L. G. Corral, et al., Ann. Rheum. Dis.58:(Suppl I) 1107-1113 (1999).

Further characterization of the selective cytokine inhibitory drugsshows that they are potent PDE4 inhibitors. PDE4 is one of the majorphosphodiesterase isoenzymes found in human myeloid and lymphoid lineagecells. The enzyme plays a crucial part in regulating cellular activityby degrading the ubiquitous second messenger cAMP and maintaining it atlow intracellular levels. Id. Inhibition of PDE4 activity results inincreased cAMP levels leading to the modulation of LPS induced cytokinesincluding inhibition of TNF-α production in monocytes as well as inlymphocytes.

3. SUMMARY OF THE INVENTION

This invention encompasses methods of treating and preventingmyeloproliferative disease (“MPD”) which comprise administering to apatient in need thereof a therapeutically or prophylactically effectiveamount of a selective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof. The invention also encompasses methods ofmanaging MPD (e.g., lengthening the time of remission) which compriseadministering to a patient in need of such management a therapeuticallyor prophylactically effective amount of a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.

One embodiment of the invention encompasses the use of one or moreselective cytokine inhibitory drugs in combination with conventionaltherapies presently used to treat, prevent or manage MPD such as, butnot limited to, hydroxyurea, anagrelide, interferons, kinase inhibitors,cancer chemotherapeutics, stem cell transplantations and othertransplantations.

Another embodiment of the invention encompasses a method of reducing orpreventing an adverse effect associated with MPD therapy, whichcomprises administering to a patient in need of such treatment orprevention an amount of a selective cytokine inhibitory drug of theinvention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof, that is sufficient toreduce an adverse effect associated with the MPD therapy. Thisembodiment includes the use of a selective cytokine inhibitory drug ofthe invention to protect against or treat an adverse effect associatedwith the use of the MPD therapy. This embodiment encompasses raising apatient's tolerance for the MPD therapy.

Another embodiment of the invention encompasses a method of increasingthe therapeutic efficacy of a MPD treatment which comprisesadministering to a patient in need of such increased therapeuticefficacy an amount of a selective cytokine inhibitory drug of theinvention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof, that is sufficient toincrease the therapeutic efficacy of the MPD treatment.

The invention further encompasses pharmaceutical compositions, singleunit dosage forms, and kits suitable for use in treating, preventingand/or managing MPD, which comprise a selective cytokine inhibitory drugof the invention, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof.

4. DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention encompasses methods of treating orpreventing MPD, which comprise administering to a patient in need ofsuch treatment or prevention a therapeutically or prophylacticallyeffective amount of a selective cytokine inhibitory drug, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof. The embodiment encompasses the treatment,prevention or management of specific sub-types of SPD such as, but notlimited to, polycythemia rubra vera (PRV), primary thromobocythemia(PT), chronic myelogenous leukemia (CML), and agnogenic myeloidmetaplasia (AMM).

As used herein, the term “myeloproliferative disease,” or “MPD,” means ahematopoietic stem cell disorder characterized by one or more of thefollowing: clonal expansion of a multipotent hematopoietic progenitorcell with the overproduction of one or more of the formed elements ofthe blood (e.g. elevated red blood cell count, elevated white blood cellcount, and/or elevated platelet count), presence of Philadelphiachromosome or bcr-abl gene, teardrop poikilocytosis on peripheral bloodsmear, leukoerythroblastic blood pictuer, giant abnormal platelets,hypercellular bone marrow with reticular or collagen fibrosis, markedleft-shifted myeloid series with a low percentage of promyelocytes andblasts, splenomegaly, thrombosis, risk of progression to acute leukemiaor cellular marrow with impaired morphology. The term“myeloproliferative disease,” or “MPD,” unless otherwise noted includes:polycythemia rubra vera (PRV), primary thromobocythemia (PT), chronicmyelogenous leukemia (CML), and agnogenic myeloid metaplasia (AMM). In aspecific embodiment, the term “myeloproliferative disease” or “MPD”excludes leukemia Particular types of MPD are PRV, PT, CML and AMM.

Another embodiment of the invention encompasses methods of managing WDwhich comprises administering to a patient in need of such management aprophylactically effective amount of a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof.

Another embodiment of the invention encompasses a pharmaceuticalcomposition comprising a selective cytokine inhibitory drug, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

Also encompassed by the invention are single unit dosage formscomprising a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof.

Another embodiment of the invention encompasses a method of treating,preventing and/or managing MPD, which comprises administering to apatient in need of such treatment, prevention and/or management atherapeutically or prophylactically effective amount of a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and atherapeutically or prophylactically effective amount of a second activeagent.

Examples of second active agents include, but are not limited to,cytokines, corticosteroids, ribonucleotide reductase inhibitors,platelet inhibitors, all-trans retinoic acids, kinase inhibitors,topoisomerase inhibitors, farnesyl transferase inhibitors, antisenseoligonucleotides, vaccines, anti-cancer agents, anti-fungal agents,anti-inflammatory agents, immunosuppressive or myelosuppressive agents,and conventional therapies for MPD.

Without being limited by theory, it is believed that certain selectivecytokine inhibitory drugs can act in complementary or synergistic wayswith conventional and other therapies in the treatment or management ofMPD. It is also believed that certain selective cytokine inhibitorydrugs act by different mechanisms than conventional and other therapiesin the treatment or management of MPD. In addition, it is believed thatcertain selective cytokine inhibitory drugs are effective whenadministered to patients who are refractory to conventional treatmentsfor myeloproliferative diseases as well as treatments using thalidomide.As used herein, the term “refractory” means the patient's response to aMPD treatment is not satisfactory by clinical standards, e.g., show noor little improvement of symptoms or laboratory findings.

It is also believed that certain therapies may reduce or eliminateparticular adverse effects associated with some selective cytokineinhibitory drugs of the invention, thereby allowing the administrationof larger amounts of a selective cytokine inhibitory drug to patientsand/or increasing patient compliance. It is further believed that someselective cytokine inhibitory drugs may reduce or eliminate particularadverse effects associated with other MPD therapies, thereby allowingthe administration of larger amounts of such therapies to patientsand/or increasing patient compliance.

Another embodiment of the invention encompasses a kit comprising: apharmaceutical composition comprising a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof and a second active agentand/or instructions for use. The invention further encompasses kitscomprising single unit dosage forms.

Another embodiment of the invention encompasses a method of reversing,reducing or avoiding an adverse effect associated with theadministration of an active agent used to treat MPD in a patientsuffering from MPD, which comprises administering to a patient in needthereof a therapeutically or prophylactically effective amount of aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.Examples of active agents include, but are not limited to, the secondactive agents described herein (see section 4.2.).

Examples of adverse effects associated with active agents used to treatMPD include, but are not limited to: conversion to acute leukemia;severe myelosuppression; gastrointestinal toxicity such as, but notlimited to, early and late-forming diarrhea and flatulence;gastrointestinal bleeding; nausea; vomiting; anorexia; leukopenia;anemia; neutropenia; asthenia; abdominal cramping; fever; pain; loss ofbody weight; dehydration; alopecia; dyspnea; insomnia; dizziness,mucositis, xerostomia, mucocutaneous lesions, and kidney failure.

As leukemic transformation develops in certain stages of MPD,transplantation of peripheral blood stem cells, hematopoietic stem cellpreparation or bone marrow may be necessary. Without being limited bytheory, it is believed that the combined use of a selective cytokineinhibitory drug and the transplantation of stem cells in a patientsuffering from MPD provides a unique and unexpected synergism. Inparticular, it is believed that a selective cytokine inhibitory drugexhibits immunomodulatory activity that can provide additive orsynergistic effects when given concurrently with transplantationtherapy. Selective cytokine inhibitory drugs of the invention can workin combination with transplantation therapy to reduce complicationsassociated with the invasive procedure of transplantation and risk ofrelated Graft Versus Host Disease (GVHD). Therefore, this inventionencompasses a method of treating, preventing and/or managing MPD, whichcomprises administering to a patient (e.g., a human) a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before,during, or after transplantation therapy.

The invention also encompasses pharmaceutical compositions, single unitdosage forms, and kits which comprise one or more selective cytokineinhibitory drugs of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, asecond active ingredient, and/or blood or cells for transplantationtherapy. For example, a kit may contain one or more compounds of theinvention, stem cells for transplantation and an immunosuppressiveagent, and an antibiotic or other drug.

4.1 Selective Cytokine Inhibitory Drugs

Compounds used in the invention include racemic, stereomerically pureand stereomerically enriched selective cytokine inhibitory drugs,stereomerically and enantiomerically pure compounds that have selectivecytokine inhibitory activities, and pharmaceutically acceptable salts,solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.Preferred compounds used in the invention are known Selective CytokineInhibitory Drugs (SelCIDs™) of Celgene Corporation, NJ.

As used herein and unless otherwise indicated, the terms “selectivecytokine inhibitory drugs” and “SelCIDs™” encompass small moleculedrugs, e.g., small organic molecules which are not peptides, proteins,nucleic acids, oligosaccharides or other macromolecules. Preferredcompounds inhibit TNF-α production. Compounds may also have a modestinhibitory effect on LPS induced IL1β and IL12. More preferably, thecompounds of the invention are potent PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include, butare not limited to, the cyclic imides disclosed in U.S. Pat. Nos.5,605,914 and 5,463,063; the cycloalkyl amides and cycloalkyl nitrilesof U.S. Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and6,518,281; the aryl amides (for example, an embodiment beingN-benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)-propanamide) of U.S. Pat.Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780; the imide/amideethers and alcohols (for example,3-phthalimido-3-(3′,4′-dimethoxyphenyl)propan-1-ol) disclosed in U.S.Pat. No. 5,703,098; the succinimides and maleimides (for example methyl3-(3′,4′,5′6′-petrahydrophthalimdo)-3-(3″,4″-dimethoxyphenyl)propionate)disclosed in U.S. Pat. No. 5,658,940; imido and amido substitutedalkanohydroxamic acids disclosed in U.S. Pat. No. 6,214,857 and WO99/06041; substituted phenethylsulfones disclosed in U.S. Pat. Nos.6,011,050 and 6,020,358; fluoroalkoxy-substituted 1,3-dihydro-isoindolylcompounds disclosed in U.S. patent application Ser. No. 10/748,085 filedon Dec. 29, 2003; substituted imides (for example,2-phthalimido-3-(3′,4′-dimethoxyphenyl)propane) disclosed in U.S. Pat.No. 6,429,221; substituted 1,3,4-oxadiazoles (for example,2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazole-2-yl)ethyl]-5-methylisoindoline-1,3-dione)disclosed in U.S. Pat. No. 6,326,388; cyano and carboxy derivatives ofsubstituted styrenes (for example,3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile) disclosed in U.S. Pat. Nos.5,929,117, 6,130,226, 6,262,101 and 6,479,554; isoindoline-1-one andisoindoline-1,3-dione substituted in the 2-position with anα-(3,4-disubstituted phenyl)alkyl group and in the 4- and/or 5-positionwith a nitrogen-containing group disclosed in WO 01/34606 and U.S. Pat.No. 6,667,316; and imido and amido substituted acylhydroxamic acids (forexample,(3-(1,3-dioxoisoindoline-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoylamino)propanoate disclosed in WO 01/45702 and U.S. Pat. No. 6,699,899. Otherselective cytokine inhibitory drugs include diphenylethylene compoundsdisclosed in U.S. provisional application No. 60/452,460, filed Mar. 5,2003, the contents of which are incorporated by reference herein intheir entirety. The entireties of each of the patents and patentapplications identified herein are incorporated herein by reference.

Additional selective cytokine inhibitory drugs belong to a family ofsynthesized chemical compounds of which typical embodiments include3-(1,3-dioxobenzo-[f]isoindol-2-yl)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamideand3-(1,3-dioxo-4-azaisoindol-2-yl)-3-(3,4-dimethoxyphenyl)-propionamide.

Other specific selective cytokine inhibitory drugs belong to a class ofnon-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579,5,877,200, 6,075,041 and 6,200,987, and WO 95/01348, each of which isincorporated herein by reference. Representative cyclic amides includecompounds of the formula:

wherein n has a value of 1, 2, or 3;

R⁵ is o-phenylene, unsubstituted or substituted with 1 to 4 substituentseach selected independently from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino,acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms,and halo;

R⁷ is (i) phenyl or phenyl substituted with one or more substituentseach selected independently of the other from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzylunsubstituted or substituted with 1 to 3 substituents selected from thegroup consisting of nitro, cyano, trifluoromethyl, carboethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, (iii) naphthyl, and (iv) benzyloxy;

R¹² is —OH, alkoxy of 1 to 12 carbon atoms, or

R⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, —COR¹⁰, or —SO₂R¹⁰,wherein R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

Specific compounds of this class include, but are not limited to:

-   3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid;-   3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide;-   3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid;-   3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide;-   3-(4-methoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid;-   3-(4-methoxyphenyl)-3-(1-oxoisoindolin-yl)propionamide;-   3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid;-   3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydroisoindol-2-yl)propionamide;-   3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide;-   3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid;-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionate;-   3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionic    acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionic acid;-   3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionamide;-   3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionamide;-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionate; and-   methyl    3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionate.

Other representative cyclic amides include compounds of the formula:

in which Z is:

in which:

R¹ is the divalent residue of (i) 3,4-pyridine, (ii) pyrrolidine, (iii)imidizole, (iv) naphthalene, (v) thiophene, or (vi) a straight orbranched alkane of 2 to 6 carbon atoms, unsubstituted or substitutedwith phenyl or phenyl substituted with nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamyl, acetoxy,carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, or halo, wherein the divalent bonds of said residue areon vicinal ring carbon atoms;

R² is —CO— or —SO₂—;

R³ is (i) phenyl substituted with 1 to 3 substituents each selectedindependently from nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, or halo, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (iv)naphthyl, (vi) thienyl, (vii) quinolyl, (viii) furyl, or (ix) indolyl;

R⁴ is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leucyl,isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl,threonyl, thyronyl, tyrosyl, valyl, benzimidol-2-yl, benzoxazol-2-yl,phenylsulfonyl, methylphenylsulfonyl, or phenylcarbamoyl; and

n has a value of 1, 2, or 3. Other representative cyclic amides includecompounds of the formula:

in which R⁵ is (i) o-phenylene, unsubstituted or substituted with 1 to 4substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino,acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, or halo, or (ii) the divalent residue of pyridine, pyrrolidine,imidizole, naphthalene, or thiophene, wherein the divalent bonds are onvicinal ring carbon atoms;

R⁶ is —CO—, —CH₂—, or —SO₂—;

R⁷ is (i) hydrogen if R⁶ is —SO₂—, (ii) straight, branched, or cyclicalkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, (v)alkyl of 1 to 10 carbon atoms, (vi) benzyl unsubstituted or substitutedwith 1 to 3 substituents selected from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (vii) naphthyl, (viii)benzyloxy, or (ix) imidazol-4-yl methyl;

R¹² is —OH, alkoxy of 1 to 12 carbon atoms, or

n has a value of 0, 1, 2, or 3;

R^(8′) is hydrogen or alkyl of 1 to 10 carbon atoms; and

R^(9′) is hydrogen, alkyl of 1 to 10 carbon atoms, —COR¹⁰, or —SO₂R¹⁰ inwhich R¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

Other representative imides include compounds of the formula:

in which R⁷ is (i) straight, branched, or cyclic alkyl of 1 to 12 carbonatoms, (ii) pyridyl, (iii) phenyl or phenyl substituted with one or moresubstituents each selected independently of the other from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (iv) benzylunsubstituted or substituted with one to three substituents selectedfrom the group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo, (v) napthyl, (vi) benzyloxy, or (vii)imidazol-4-ylmethyl;

R¹² is —OH, alkoxy of 1 to 12 carbon atoms, —O—CH₂-pyridyl, —O-benzyl or

where n has a value of 0, 1, 2, or 3;

R^(8′) is hydrogen or alkyl of 1 to 10 carbon atoms; and

R^(9′) is hydrogen, alkyl of 1 to 10 carbon atoms, —CH₂-pyridyl, benzyl,—COR¹⁰, or —SO₂R¹⁰ in which R¹⁰ is hydrogen, alkyl of 1 to 4 carbonatoms, or phenyl.

Other specific selective cytokine inhibitory drugs include the imido andamido substituted alkanohydroxamic acids disclosed in WO 99/06041 andU.S. Pat. No. 6,214,857, each of which is incorporated herein byreference. Examples of such compound include, but are not limited to:

wherein each of R¹ and R², when taken independently of each other, ishydrogen, lower alkyl, or R¹ and R², when taken together with thedepicted carbon atoms to which each is bound, is o-phenylene,o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substitutedwith 1 to 4 substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms,alkoxy of 1 to 10 carbon atoms, and halo;

R³ is phenyl substituted with from one to four substituents selectedfrom the group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to6 carbon atoms, C₄-C₆-cycloalkylidenemethyl, C₃-C₁₀-alkylidenemethyl,indanyloxy, and halo;

R⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;

R^(4′) is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵ is —CH₂—, —CH₂—CO—, —SO₂—, —S—, or —NHCO—; and

n has a value of 0, 1, or 2; and

the acid addition salts of said compounds which contain a nitrogen atomcapable of being protonated.

Additional specific selective cytokine inhibitory drugs used in theinvention include, but are not limited to:

-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)propionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide;-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methyl-phthalimido)propionamide;-   3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide;-   N-hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide;-   3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-N-hydroxypropionamide;-   3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;-   3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;-   N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;-   3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)    propionamide; and-   N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propionamide.

Additional selective cytokine inhibitory drugs used in the inventioninclude the substituted phenethylsulfones substituted on the phenylgroup with a oxoisoindine group. Examples of such compounds include, butare not limited to, those disclosed in U.S. Pat. No. 6,020,358, which isincorporated herein by reference, which include the following:

wherein the carbon atom designated * constitutes a center of chirality;

Y is C═O, CH₂, SO₂, or CH₂C═O; each of R¹, R², R³, and R⁴, independentlyof the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxyof 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR⁸R⁹; or any two ofR¹, R², R³, and R⁴ on adjacent carbon atoms, together with the depictedphenylene ring are naphthylidene;

each of R⁵ and R⁶, independently of the other, is hydrogen, alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxyof up to 18 carbon atoms;

R⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, orNR^(8′)R^(9′);

each of R⁸ and R⁹ taken independently of the other is hydrogen, alkyl of1 to 8 carbon atoms, phenyl, or benzyl, or one of R⁸ and R⁹ is hydrogenand the other is —COR¹⁰ or —SO₂R¹⁰, or R⁸ and R⁹ taken together aretetramethylene, pentamethylene, hexamethylene, or —CH₂CH₂X¹CH₂CH₂— inwhich X¹ is —O—, —S— or —NH—; and

each of R^(8′) and R^(9′) taken independently of the other is hydrogen,alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R^(8′) andR^(9′) is hydrogen and the other is —COR^(10′) or —SO₂R^(10′), or R^(8′)and R^(9′) taken together are tetramethylene, pentamethylene,hexamethylene, or —CH₂CH₂X²CH₂CH₂— in which X² is —O—, —S—, or —NH—.

It will be appreciated that while for convenience the above compoundsare identified as phenethylsulfones, they include sulfonamides when R⁷is NR^(8′)R^(9′).

Specific groups of such compounds are those in which Y is C═O or CH₂.

A further specific group of such compounds are those in which each ofR¹, R², R³, and R⁴ independently of the others, is hydrogen, halo,methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or —NR⁸R⁹ inwhich each of R⁸ and R⁹ taken independently of the other is hydrogen ormethyl or one of R⁸ and R⁹ is hydrogen and the other is —COCH₃.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—NH₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—NHCOCH₃ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ is—N(CH₃)₂ and the remaining of R¹, R², R³, and R⁴ are hydrogen.

A further preferred group of such compounds are those in which one ofR¹, R², R³, and R⁴ is methyl and the remaining of R¹, R², R³, and R⁴ arehydrogen.

Particular compounds are those in which one of R¹, R², R³, and R⁴ isfluoro and the remaining of R¹, R², R³, and R⁴ are hydrogen.

Particular compounds are those in which each of R⁵ and R⁶, independentlyof the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy,propoxy, cyclopentoxy, or cyclohexoxy.

Particular compounds are those in which R⁵ is methoxy and R⁶ ismonocycloalkoxy, polycycloalkoxy, and benzocycloalkoxy.

Particular compounds are those in which R⁵ is methoxy and R⁶ is ethoxy.

Particular compounds are those in which R⁷ is hydroxy, methyl, ethyl,phenyl, benzyl, or NR^(8′)R^(9′) in which each of R^(8′) and R^(9′)taken independently of the other is hydrogen or methyl.

Particular compounds are those in which R⁷ is methyl, ethyl, phenyl,benzyl or NR^(8′)R^(9′) in which each of R^(8′) and R^(9′) takenindependently of the other is hydrogen or methyl.

Particular compounds are those in which R⁷ is methyl.

Particular compounds are those in which R⁷ is NR^(8′)R^(9′) in whicheach of R^(8′) and R^(9′) taken independently of the other is hydrogenor methyl.

Additional selective cytokine inhibitory drugs includefluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds disclosed inU.S. patent application Ser. No. 10/748,085 filed on Dec. 29, 2003,which is incorporated herein by reference. Representative compounds areof formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)—, —C(O)CH₂—, or SO₂;

Z is —H, —C(O)R³, —(C₀₋₁-alkyl)-SO₂—(C₁₋₄-alkyl), —C₁₋₈-alkyl, —CH₂OH,CH₂(O)(C₁₋₈-alkyl) or —CN;

R₁ and R₂ are each independently —CHF₂, —C₁₋₈-alkyl, —C₃₋₁₈-cycloalkyl,or —(C₁₋₁₀-alkyl)(C₃₋₁₈-cycloalkyl), and at least one of R₁ and R₂ isCHF₂;

R³ is —NR⁴R⁵, -alkyl, —OH, —O-alkyl, phenyl, benzyl, substituted phenyl,or substituted benzyl;

R⁴ and R⁵ are each independently-H, —C₁₋₈-alkyl, —OH, —OC(O)R⁶;

R⁶ is —C₁₋₈-alkyl, -amino(C₁₋₈-alkyl), -phenyl, -benzyl, or -aryl;

X₁, X₂, X₃, and X₄ are each independently —H, -halogen, -nitro, —NH₂,—CF₃, —C₁₋₆-alkyl, —(C₀₋₄-alkyl)-(C₃₋₆-Cycloalkyl), (C₀₋₄-alkyl)-NR⁷R⁸,(C₀₋₄-alkyl)-N(H)C(O)—(R⁸), (C₀₋₄-alkyl)-N(H)C(O)N(R⁷R⁸),(C₀₋₄-alkyl)-N(H)C(O)O(R⁷R⁸), (C₀₋₄-alkyl)-OR⁸, (C₀₋₄-alkyl)-imidazolyl,(C₀₋₄-alkyl)-pyrrolyl, (C₀₋₄-alkyl)-oxadiazolyl, or(C₀₋₄-alkyl)-triazolyl, or two of X₁, X₂, X₃, and X₄ may be joinedtogether to form a cycloalkyl or heterocycloalkyl ring, (e.g., X₁ andX₂, X₂ and X₃, X₃ and X₄, X₁ and X₃, X₂ and X₄, or X₁ and X₄ may form a3, 4, 5, 6, or 7 membered ring which may be aromatic, thereby forming abicyclic system with the isoindolyl ring); and

R⁷ and R⁸ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₁₋₆-alkyl)-N(R⁷R⁸), (C₁₋₆-alkyl)-OR⁸,phenyl, benzyl, or aryl; or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof.

Additional selective cytokine inhibitory drugs include theenantiomerically pure compounds disclosed in U.S. patent applicationSer. No. 10/392,195 filed on Mar. 19, 2003; international patentapplication nos. PCT/US03/08737 and PCT/US03/08738, filed on Mar. 20,2003; U.S. provisional patent application Nos. 60/438,450 and 60/438,448to G. Muller et al., both of which were filed on Jan. 7, 2003; U.S.provisional patent application No. 60/452,460 to G. Muller et al. filedon Mar. 5, 2003; and U.S. patent application Ser. No. 10/715,184 filedon Nov. 17, 2003, all of which are incorporated herein by reference.Preferred compounds include an enantiomer of2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dioneand an enantiomer of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide.

Preferred selective cytokine inhibitory drugs used in the invention are3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideand cyclopropanecarboxylic acid{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide,which are available from Celgene Corp., Warren, N.J.3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidehas the following chemical structure:

Other specific selective cytokine inhibitory drugs include, but are notlimited to, the cycloalkyl amides and cycloalkyl nitrites of U.S. Pat.Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281, and WO97/08143 and WO 97/23457, each of which is incorporated herein byreference. Representative compounds are of formula:

wherein:

one of R¹ and R² is R³—X— and the other is hydrogen, nitro, cyano,trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, or R³—X—;

R³ is monocycloalkyl, bicycloalkyl, or benzocycloalkyl of up to 18carbon atoms;

X is a carbon-carbon bond, —CH₂—, or —O—;

R⁵ is (i) o-phenylene, unsubstituted or substituted with 1 to 3substituents each selected independently from nitro, cyano, halo,trifluoromethyl, carbo(lower)alkoxy, acetyl, or carbamoyl, unsubstitutedor substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, loweralkylamino, lower acylamino, or lower alkoxy; (ii) a vicinally divalentresidue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene,wherein the divalent bonds are on vicinal ring carbon atoms; (iii) avicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms,unsubstituted or substituted with 1 to 3 substituents each selectedindependently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, orphenyl; (iv) vinylene di-substituted with lower alkyl; or (v) ethylene,unsubstituted or monosubstituted or disubstituted with lower alkyl;

R⁶ is —CO—, —CH₂—, or —CH₂CO—;

Y is —COZ, —C≡N, —OR⁸, lower alkyl, or aryl;

Z is —NH₂, —OH, —NHR, —R⁹, or —OR⁹

R⁸ is hydrogen or lower alkyl;

R⁹ is lower alkyl or benzyl; and,

n has a value of 0, 1, 2, or 3.

In another embodiment, one of R¹ and R² is R³—X— and the other ishydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy,halo, or R³—X—;

R³ is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms;

X is —CH₂—, or —O—;

R⁵ is (i) the vicinally divalent residue of pyridine, pyrrolidine,imidazole, naphthalene, or thiophene, wherein the two bonds of thedivalent residue are on vicinal ring carbon atoms;

(ii) a vicinally divalent cycloalkyl of 4-10 carbon atoms, unsubstitutedor substituted with 1 to 3 substituents each selected independently fromthe group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, or phenyl;

(iii) di-substituted vinylene, substituted with nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo;

(iv) ethylene, unsubstituted or substituted with 1 to 2 substituentseach selected independently from nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoylsubstituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy,hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms,alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo;

R⁶ is —CO—, —CH₂—, or —CH₂CO—;

Y is —COX, —C≡N, —OR⁸, alkyl of 1 to 5 carbon atoms, or aryl;

X is —NH₂, —OH, —NHR, —R⁹, —OR⁹, or alkyl of 1 to 5 carbon atoms;

R⁸ is hydrogen or lower alkyl;

R⁹ is alkyl or benzyl; and,

n has a value of 0, 1, 2, or 3.

In another embodiment, one of R¹ and R² is R³—X— and the other ishydrogen, nitro, cyano, trifluoromethyl, carbo(lower)alkoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy,halo, HF₂CO, F₃CO, or R³—X—;

R³ is monocycloalkyl, bicycloalkyl, benzocyclo alkyl of up to 18 carbonatoms, tetrahydropyran, or tetrahydrofuran;

X is a carbon-carbon bond, —CH₂—, —O—, or —N═;

R⁵ is (i) o-phenylene, unsubstituted or substituted with 1 to 3substituents each selected independently from nitro, cyano, halo,trifluoromethyl, carbo(lower)alkoxy, acetyl, or carbamoyl, unsubstitutedor substituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, loweralkylamino, lower acylamino, or lower alkoxy; (ii) a vicinally divalentresidue of pyridine, pyrrolidine, imidazole, naphthalene, or thiophene,wherein the divalent bonds are on vicinal ring carbon atoms; (iii) avicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms,unsubstituted or substituted with 1 or more substituents each selectedindependently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbo(lower)alkoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy, orphenyl; (iv) vinylene di-substituted with lower alkyl; or (v) ethylene,unsubstituted or monosubstituted or disubstituted with lower alkyl;

R⁶ is —CO—, —CH₂—, or —CH₂CO—;

Y is —COX, —C≡N, —OR⁸, alkyl of 1 to 5 carbon atoms, or aryl;

X is —NH₂, —OH, —NHR, —R⁹, —OR⁹, or alkyl of 1 to 5 carbon atoms;

R⁸ is hydrogen or lower alkyl;

R⁹ is alkyl or benzyl; and,

n has a value of 0, 1, 2, or 3.

Other representative compounds are of formula:

wherein:

Y is —C≡N or CO(CH₂)_(m)CH₃;

m is 0, 1, 2, or 3;

R⁵ is (i) o-phenylene, unsubstituted or substituted with 1 to 3substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo; (ii) the divalent residue of pyridine, pyrrolidine,imidizole, naphthalene, or thiophene, wherein the divalent bonds are onvicinal ring carbon atoms; (iii) a divalent cycloalkyl of 4-10 carbonatoms, unsubstituted or substituted with one or more substituents eachselected independently of the other from the group consisting of nitro,cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo;(iv) di-substituted vinylene, substituted with nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo; or (v) ethylene, unsubstituted or substituted with 1 to2 substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo;

R⁶ is —CO—, —CH₂—, —CH₂CO—, or —SO₂—;

R⁷ is (i) straight or branched alkyl of 1 to 12 carbon atoms; (ii)cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (iii) pyridyl; (iv)phenyl substituted with one or more substituents each selectedindependently of the other from nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkylof 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxyof 1 to 10 carbon atoms, CH₂R where R is a cyclic or bicyclic alkyl of 1to 10 carbon atoms, or halo; (v) benzyl substituted with one to threesubstituents each selected independently from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (vi) naphthyl; or(vii) benzyloxy; and

n has a value of 0, 1, 2, or 3.

In another embodiment, specific selective cytokine inhibitory drugs areof formula:

wherein:

R⁵ is (i) the divalent residue of pyridine, pyrrolidine, imidizole,naphthalene, or thiophene, wherein the divalent bonds are on vicinalring carbon atoms; (ii) a divalent cycloalkyl of 4-10 carbon atoms,unsubstituted or substituted with one or more substituents each selectedindependently of the other from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo;(iii) di-substituted vinylene, substituted with nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo; or (iv) ethylene, unsubstituted or substituted with 1 to2 substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, or halo;

R⁶ is —CO—, —CH₂—, —CH₂CO—, or —SO₂—;

R⁷ is (i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms; (ii)pyridyl; (iii) phenyl substituted with one or more substituents eachselected independently of the other from nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, straight, branched, cyclic, or bicyclic alkylof 1 to 10 carbon atoms, straight, branched, cyclic, or bicyclic alkoxyof 1 to 10 carbon atoms, CH₂R where R is a cyclic or bicyclic alkyl of 1to 10 carbon atoms, or halo; (iv) benzyl substituted with one to threesubstituents each selected independently from the group consisting ofnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo; (v) naphthyl; or(vi) benzyloxy; and

Y is COX, —C≡N, OR⁸, alkyl of 1 to 5 carbon atoms, or aryl;

X is —NH₂, —OH, —NHR, —R⁹, —OR⁹, or alkyl of 1 to 5 carbon atoms;

R⁸ is hydrogen or lower alkyl;

R⁹ is alkyl or benzyl; and

n has a value of 0, 1, 2, or 3.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, the aryl amides (for example, an embodiment beingN-benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)-propanamide) of U.S. Pat.Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780, each of which isincorporated herein by reference. Representative compounds are offormula:

wherein:

Ar is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1to 12 carbon atoms; (iii) phenyl; (iv) phenyl substituted with one ormore substituents each selected independently of the other from thegroup consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, or halo; (v) heterocycle; or (vi) heterocyclesubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;

R is —H, alkyl of 1 to 10 carbon atoms, CH₂OH, CH₂CH₂OH, or CH₂COZ whereZ is alkoxy of 1 to 10 carbon atoms, benzyloxy, or NHR¹ where R¹ is H oralkyl of 1 to 10 carbon atoms; and

Y is i) a phenyl or heterocyclic ring, unsubstituted or substituted oneor more substituents each selected independently one from the other fromnitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy,acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo or ii) naphthyl.Specific examples of the compounds are of formula:

wherein:

Ar is 3,4-disubstituted phenyl where each substituent is selectedindependently of the other from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, and halo;

Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, amino, or alkylamino of1 to 10 carbon atoms; and

Y is (i) a phenyl, unsubstituted or substituted with one or moresubstituents each selected, independently one from the other, from thegroup consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbonatoms, and halo, or (ii) naphthyl.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, the imide/amide ethers and alcohols (for example,3-phthalimido-3-(3′,4′-dimethoxyphenyl) propan-1-ol) disclosed in U.S.Pat. No. 5,703,098, which is incorporated herein by reference.Representative compounds have the formula:

wherein:

R¹ is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one ormore substituents each selected independently of the other from thegroup consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, acylamino, alkylamino, di(alkyl)amino, alkyl of 1 to 10carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, and halo;

R² is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl, oralkoxymethyl;

R³ is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v)cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted withone or more substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, aminosubstituted with alkyl of 1 to 6 carbon atoms, amino substituted withacyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1to 12 carbon atoms, and halo, (vi) cycloalkenylene of 4 to 9 carbonatoms unsubstituted or substituted with one or more substituents eachselected independently from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted withalkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbonatoms, and halo, (vii) o-phenylene unsubstituted or substituted with oneor more substituents each selected independently from the groupconsisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, aminosubstituted with alkyl of 1 to 6 carbon atoms, amino substituted withacyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1to 12 carbon atoms, and halo, (viii) naphthyl, or (ix) pyridyl;

R⁴ is —CX—, —CH₂— or —CH₂CX—;

X is O or S; and

n is 0, 1, 2, or 3.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, the succinimides and maleimides (for example methyl3-(3′,4′,5′6′-petrahydrophthalimdo)-3-(3″,4″-dimethoxyphenyl)propionate)disclosed in U.S. Pat. No. 5,658,940, which is incorporated herein byreference. Representative compounds are of formula:

wherein:

R¹ is —CH₂—, —CH₂CO—, or —CO—;

R² and R³ taken together are (i) ethylene unsubstituted or substitutedwith alkyl of 1-10 carbon atoms or phenyl, (ii) vinylene substitutedwith two substituents each selected, independently of the other, fromthe group consisting of alkyl of 1-10 carbon atoms and phenyl, or (iii)a divalent cycloalkyl of 5-10 carbon atoms, unsubstituted or substitutedwith one or more substituents each selected independently of the otherfrom the group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl unsubstituted orsubstituted with alkyl of 1-3 carbon atoms, acetoxy, carboxy, hydroxy,amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to10 carbon atoms, norbornyl, phenyl or halo;

R⁴ is (i) straight or branched unsubstituted alkyl of 4 to 8 carbonatoms, (ii) cycloalkyl or bicycloalkyl of 5-10 carbon atoms,unsubstituted or substituted with one or more substituents each selectedindependently of the other from the group consisting of nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino,branched, straight or cyclic alkyl of 1 to 10 carbon atoms, alkoxy of 1to 10 carbon atoms, phenyl or halo, (iii) phenyl substituted with one ormore substituents each selected independently of the other from thegroup consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, cycloalkyl or bicycloalkyl of 3 to 10 carbonatoms, cycloalkoxy or bicycloalkoxy of 3 to 10 carbon atoms, phenyl orhalo, (iv) pyridine or pyrrolidine, unsubstituted or substituted withone or more substituents each selected independently of the other fromthe group consisting of nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, phenyl or halo; and,

R⁵ is —COX, —CN, —CH₂COX, allyl of 1 to 5 carbon atoms, aryl, —CH₂OR,—CH₂ aryl, or —CH₂OH,

where X is NH₂, OH, NHR, or OR⁶,

where R is lower alkyl; and

where R⁶ is alkyl or benzyl.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, substituted imides (for example,2-phthalimido-3-(3′,4′-dimethoxyphenyl)propane) disclosed in U.S. Pat.No. 6,429,221, which is incorporated herein by reference. Representativecompounds have the formula:

wherein:

R¹ is (i) straight, branched, or cyclic alkyl of 1 to 12 carbon atoms,(ii) phenyl or phenyl substituted with one or more substituents eachselected independently of the other from nitro, cyano, trifluoromethyl,carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy,carboxy, hydroxy, amino, straight or branched alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo, (iii) benzyl or benzylsubstituted with one or more substituents each selected independently ofthe other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylof 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or(iv) —Y-Ph where Y is a straight, branched, or cyclic alkyl of 1 to 12carbon atoms and Ph is phenyl or phenyl substituted with one or moresubstituents each selected independently of the other from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbonatoms, alkoxy of 1 to 10 carbon atoms, or halo;

R² is —H, a branched or unbranched alkyl of 1 to 10 carbon atoms,phenyl, pyridyl, heterocycle, —CH₂-aryl, or —CH₂-heterocycle;

R³ is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10carbon atoms, iv) a branched alkenylene of 3 to 10 carbon atoms, v)cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1to 2 substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, vi)cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with1 to 2 substituents each selected independently from nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo, or vii)o-phenylene unsubstituted or substituted with 1 to 2 substituents eachselected independently from nitro, cyano, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy1 to 4 carbon atoms, or halo; and,

R⁴ is —CX, or —CH₂—;

X is O or S.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, substituted 1,3,4-oxadiazoles (for example,2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazole-2-yl)ethyl]-5-methylisoindoline-1,3-dione)disclosed in U.S. Pat. No. 6,326,388, which is incorporated herein byreference. Representative compounds are of formula:

wherein:

the carbon atom designated * constitutes a center of chirality;

Y is C═O, CH₂, SO₂ or CH₂C═O;

X is hydrogen, or alkyl of 1 to 4 carbon atoms;

each of R¹, R², R³, and R⁴, independently of the others, is hydrogen,halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1to 4 carbon atoms, nitro, cyano, hydroxy, —CH₂NR⁸R⁹, —(CH₂)₂NR⁸R⁹, or—NR⁸R⁹ or

any two of R¹, R², R³, and R⁴ on adjacent carbon atoms, together withthe depicted benzene ring are naphthylidene, quinoline, quinoxaline,benzimidazole, benzodioxole or 2-hydroxybenzimidazole;

each of R⁵ and R⁶, independently of the other, is hydrogen, alkyl of 1to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano,benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicyloalkoxy ofup to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, orcycloalkylalkoxy of up to 18 carbon atoms;

each of R⁸ and R⁹, taken independently of the other is hydrogen,straight or branched alkyl of 1 to 8 carbon atoms, phenyl, benzyl,pyridyl, pyridylmethyl, or one of R⁸ and R⁹ is hydrogen and the other is—COR¹⁰, or —SO₂R¹⁰, or R⁸ and R⁹ taken together are tetramethylene,pentamethylene, hexamethylene, —CH═NCH═CH—, or —CH₂CH₂X¹CH₂CH₂— in whichX¹ is —O—, —S—, or —NH—

R¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl,cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl,imidazolylmethyl, pyridylmethyl, NR¹¹R¹², CH₂R¹⁴R¹⁵, or NR¹¹R¹²

wherein R¹⁴ and R¹⁵, independently of each other, are hydrogen, methyl,ethyl, or propyl, and

wherein R¹¹ and R¹², independently of each other, are hydrogen, alkyl of1 to 8 carbon atoms, phenyl, or benzyl; and

the acid addition salts of said compounds which contain a nitrogen atomsusceptible of protonation.

Specific examples of the compounds are of formula:

wherein:

the carbon atom designated * constitutes a center of chirality;

Y is C═O, CH₂, SO₂ or CH₂C═O;

X is hydrogen, or alkyl of 1 to 4 carbon atoms;

(i) each of R¹, R², R³, and R⁴, independently of the others, ishydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms,alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, —CH₂NR⁸R⁹,—(CH₂)₂NR⁸R⁹, or —NR⁸R⁹ or

(ii) any two of R¹, R², R³, and R⁴ on adjacent carbon atoms, togetherwith the depicted benzene ring to which they are bound arenaphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or2-hydroxybenzimidazole;

each of R⁵ and R⁶, independently of the other, is hydrogen, alkyl of 1to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano,benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicyloalkoxy ofup to 18 carbon atoms, tricylcoalkoxy of up to 18 carbon atoms, orcycloalkylalkoxy of up to 18 carbon atoms;

(i) each of R⁸ and R⁹, independently of the other, is hydrogen, alkyl of1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or

(ii) one of R⁸ and R⁹ is hydrogen and the other is —COR¹⁰, or —SO₂R¹⁰,in which R¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl,cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl,imidazolylmethyl, pyridylmethyl, NR¹¹R¹², or CH₂NR¹⁴R¹⁵, wherein R¹¹ andR¹², independently of each other, are hydrogen, alkyl of 1 to 8 carbonatoms, phenyl, or benzyl and R¹⁴ and R¹⁵, independently of each other,are hydrogen, methyl, ethyl, or propyl; or

(iii) R⁸ and R⁹ taken together are tetramethylene, pentamethylene,hexamethylene, —CH═NCH═CH—, or —CH₂CH₂X¹CH₂CH₂— in which X¹ is —O—, —S—,or —NH—.

Other specific selective cytokine inhibitory drugs include, but are notlimited to, cyano and carboxy derivatives of substituted styrenes (forexample, 3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile) disclosed in U.S.Pat. Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554, each of whichis incorporated herein by reference. Representative compounds are offormula:

wherein:

(a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2, or 3,and R¹ is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclicalkyl of up to 10 carbon atoms, or

(b) X is —CH═ and R¹ is alkylidene of up to 10 carbon atoms,monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of upto 10 carbon atoms;

R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, loweralkyl, lower alkylidenemethyl, lower alkoxy, or halo;

R³ is (i) phenyl, unsubstituted or substituted with 1 or moresubstituents each selected independently from nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms,cycloalkylidenemethyl of up to 10 carbon atoms, phenyl, ormethylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine,imidizole, naphthalene, or thiophene; (iii) cycloalkyl of 4-10 carbonatoms, unsubstituted or substituted with 1 or more substituents eachselected independently from the group consisting of nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl;

each of R⁴ and R⁵ taken individually is hydrogen or R⁴ and R⁵ takentogether are a carbon-carbon bond;

Y is —COZ, —C≡N, or lower alkyl of 1 to 5 carbon atoms;

Z is —OH, —NR⁶R⁶, —R⁷, or —OR⁷; R⁶ is hydrogen or lower alkyl; and R⁷ isalkyl or benzyl. Specific examples of the compounds are of formula:

wherein:

(a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2, or 3,and R¹ is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclicalkyl of up to 10 carbon atoms, or

(b) X is —CH═ and R¹ is alkylidene of up to 10 carbon atoms,monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of upto 10 carbon atoms;

R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, loweralkyl, lower alkylidenemethyl, lower alkoxy, or halo;

R³ is pyrrolidine, imidazole or thiophene unsubstituted or substitutedwith 1 or more substituents each selected independently from the groupconsisting of nitro, cyano, halo, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, or phenyl;

each of R⁴ and R⁵ taken individually is hydrogen or R⁴ and R⁵ takentogether are a carbon-carbon bond;

Y is —COZ, —C≡N, or lower alkyl of 1 to 5 carbon atoms;

Z is —OH, —NR⁶R⁶, —R⁷, or —OR⁷; R⁶ is hydrogen or lower alkyl; and R⁷ isalkyl or benzyl.

Particularly preferred nitriles are compounds of the formula:

wherein:

(a) X is —O— or —(C_(n)H_(2n))— in which n has a value of 0, 1, 2, or 3,and R¹ is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclicalkyl of up to 10 carbon atoms, or

(b) X is —CH═, and R¹ is alkylidene of up to 10 carbon atoms ormonocycloalkylidene of up to 10 carbon atoms;

R² is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, loweralkyl, lower alkoxy, or halo; and

R³ is (i) phenyl or naphthyl, unsubstituted or substituted with 1 ormore substituents each selected independently from nitro, cyano, halo,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, or carbamoyl substituted with alkyl of 1 to 3 carbon atoms,acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or(ii) cycloalkyl of 4 to 10 carbon atoms, unsubstituted or substitutedwith one or more substituents each selected independently from the groupconsisting of nitro, cyano, halo, trifluoromethyl, carbethoxy,carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy,hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxyof 1 to 10 carbon atoms, or phenyl.

Particularly preferred nitrile is of formula:

Other specific selective cytokine inhibitory drugs include, but are notlimited to, isoindoline-1-one and isoindoline-1,3-dione substituted inthe 2-position with an α-(3,4-disubstituted phenyl)alkyl group and inthe 4- and/or 5-position with a nitrogen-containing group disclosed inWO 01/34606 and U.S. Pat. No. 6,667,316, which are incorporated hereinby reference. Representative compounds are of formula:

and include pharmaceutically acceptable salts and stereoisomers thereof,

wherein:

one of X and X′ is ═C═O or ═SO₂, and the other of X and X′ is ═C═O,═CH₂, ═SO₂ or ═CH₂C═O;

n is 1, 2 or 3;

R₁ and R₂ are each independently (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyano,(C₃-C₁₈)cycloalkyl, (C₃-C₁₈)cycloalkoxy or (C₃-C₁₈)cycloalkyl-methoxy;

R₃ is SO₂—Y, COZ, CN or (C₁-C₆)hydroxyalkyl, wherein:

Y is (C₁-C₆)alkyl, benzyl or phenyl;

Z is —NR₆R₇, (C₁-C₆)alkyl, benzyl or phenyl;

R₆ is H, (C₁-C₄)alkyl, (C₃-C₁₈)cycloalkyl, (C₂-C₅)alkanoyl, benzyl orphenyl, each of which can be optionally substituted with halo, amino or(C₁-C₄)alkyl-amino;

R₇ is H or (C₁-C₄)alkyl;

R₄ and R₅ are taken together to provide —NH—CH₂—R₈—, NH—CO—R₈—, or—N═CH—R₈—, wherein:

R₈ is CH₂, O, NH, CH═CH, CH═N, or N═CH; or

one of R₄ and R₅ is H, and the other of R₄ and R₅ is imidazoyl,pyrrolyl, oxadiazolyl, triazolyl, or a structure of formula (A),

wherein:

z is 0 or 1;

R₉ is: H; (C₁-C₄)alkyl, (C₃-C₁₈)cycloalkyl, (C₂-C₅)alkanoyl, or(C₄-C₆)cycloalkanoyl, optionally substituted with halo, amino,(C₁-C₄)alkyl-amino, or (C₁-C₄)dialkyl-amino; phenyl; benzyl; benzoyl;(C₂-C₅)alkoxycarbonyl; (C₃-C₅)alkoxyalkylcarbonyl; N-morpholinocarbonyl;carbamoyl; N-substituted carbamoyl substituted with (C₁-C₄)alkyl; ormethylsulfonyl; and

R₁₀ is H, (C₁-C₄)alkyl, methylsulfonyl, or (C₃-C₅)alkoxyalkylcarbonyl;or

R₉ and R₁₀ are taken together to provide —CH═CH—CH═CH—, —CH═CH—N═CH—, or(C₁-C₂)alkylidene, optionally substituted with amino,(C₁-C₄)alkyl-amino, or (C₁-C₄)dialkyl-amino; or

R₄ and R₅ are both structures of formula (A).

In one embodiment, z is not 0 when (i) R³ is —SO₂—Y, —COZ, or —CN and(ii) one of R⁴ or R⁵ is hydrogen. In another embodiment, R⁹ and R¹⁰,taken together, is —CH═CH—CH═CH—, —CH═CH—N═CH—, or (C₁-C₂)alkylidenesubstituted by amino, (C₁-C₄)alkyl-amino, or (C₁-C₄)dialkyl-amino. Inanother embodiment, R₄ and R₅ are both structures of formula (A).

Specific compounds are of formula:

and the enantiomers thereof. Further specific compounds are of formulas:

Further examples include, but are not limited to:2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-dinitroisoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-diaminoisoindoline-1,3-dione;7-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3-pyrrolino[3,4-e]benzimidazole-6,8-dione;7-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]hydro-3-pyrrolino[3,4-e]benzimidazole-2,6,8-trione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3-pyrrolino[3,4-f]quinoxaline-1,3-dione;Cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}carboxamide;2-Chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide;2-Amino-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide;2-N,N-Dimethylamino-N-{2-[-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}-2,2,2-trifluoroacetamide;N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-1,3-dioxoisoindolin-4-yl}methoxycarboxamide;4-[1-Aza-2-(dimethylamino)vinyl]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione;4-[1-Aza-2-(dimethylamino)prop-1-enyl]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)isoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-pyrrolylisoindoline-1,3-dione;4-(Aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-isoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione;N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1R-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1R-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1S-(3-Ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1S-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;4-Amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutylisoindoline-1,3-dione;4-Amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-3-oxobutyl]-4-pyrrolylisoindoline-1,3-dione;2-Chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindol-4-yl}acetamide;2-(Dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;4-Amino-2-[1R-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]isoindoline-1,3-dione;4-Amino-2-[1R-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione;2-[1R-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-4-pyrrolylisoindoline-1,3-dione;2-(Dimethylamino)-N-{2-[1R-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;Cyclopentyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide;3-(Dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide;2-(Dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide;N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-(dimethylamino)acetamide;N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-(dimethylamino)acetamide;4-{3[(Dimethylamino)methyl]pyrrolyl}-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione;Cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide;2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-4-pyrrolylisoindoline-1,3-dione;N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}-2-(dimethylamino)acetamide;Cyclopropyl-N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide;Cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide;2-(Dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}acetamide;Cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide;Cyclopropyl-N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide;(3R)-3-[7-(Acetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide;(3R)-3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide;3-{4-[2-(Dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide;(3R)-3-[7-(2-Chloroacetylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-N,N-dimethylpropanamide;(3R)-3-{4-[2-(dimethylamino)acetylamino]-1,3-dioxoisoindolin-2-yl}-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide;3-(1,3-Dioxo-4-pyrrolylisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-(imidazolyl-methyl)isoindoline-1,3-dione;N-({2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide;2-Chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide;2-(Dimethylamino)-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide;4-[Bis(methylsulfonyl)amino]-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione;2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-[(methylsulfonyl)amino]isoindoline-1,3-dione;N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-3-oxopentyl]1,3-dioxoisoindolin-4-yl}acetamide;2-[(1R)-1-(3-Ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione;2-[(1R)-1-(3-Ethoxy-4-methoxyphenyl)-3-oxobutyl]-4-(pyrrolylmethyl)isoindoline-1,3-dione;N-{2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide;N-{2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide;2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-3-oxobutyl]-4-pyrrolylisoindoline-1,3-dione;2-[1-(3,4-Dimethoxyphenyl)-3-oxobutyl]-4-[bis(methylsulfonyl)amino]isoindoline-1,3-dione;and pharmaceutically acceptable salts, solvates, and stereoisomersthereof.

Still other specific selective cytokine inhibitory drugs include, butare not limited to, imido and amido substituted acylhydroxamic acids(for example,(3-(1,3-dioxoisoindoline-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoylamino) propanoate disclosed in WO 01/45702 and U.S. Pat. No.6,699,899, which are incorporated herein by reference. Representativecompounds are of formula:

wherein:

the carbon atom designated * constitutes a center of chirality,

R⁴ is hydrogen or —(C═O)—R¹²,

each of R¹ and R², independently of each other, is alkyl of 1 to 6carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl,imidazolyl methyl, or

CHR*(CH₂)_(n)NR*R⁰,

wherein R* and R⁰, independently of the other, are hydrogen, alkyl of 1to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl orimidazolylmethyl, and n=0, 1, or 2;

R⁵ is C═O, CH₂, CH₂—CO—, or SO₂;

each of R⁶ and R⁷, independently of the other, is nitro, cyano,trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl,carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbonatoms, halo, bicycloalkyl of up to 18 carbon atoms, tricycloalkoxy of upto 18 carbon atoms, 1-indanyloxy, 2-indanyloxy,C₄-C₈-cycloalkylidenemethyl, or C₃-C₁₀-alkylidenemethyl;

each of R⁸, R⁹, R¹⁰, and R¹¹, independently of the others, is

(i) hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy,carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino,alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms,alkoxy of 1 to 10 carbon atoms, halo, or

(ii) one of R⁸, R⁹, R¹⁰, and R¹¹ is acylamino comprising a lower alkyl,and the remaining of R⁸, R⁹, R¹⁰, and R¹¹ are hydrogen, or

(iii) hydrogen if R⁸ and R⁹ taken together are benzo, quinoline,quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole,methylenedioxy, dialkoxy, or dialkyl, or

(iv) hydrogen if R¹⁰ and R¹¹, taken together are benzo, quinoline,quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole,methylenedioxy, dialkoxy, or dialkyl, or

(v) hydrogen if R⁹ and R¹⁰ taken together are benzo.

Still specific selective cytokine inhibitory drugs include, but are notlimited to, 7-amido-isoindolyl compounds disclosed in U.S. patentapplication Ser. No. 10/798,317 filed on Mar. 12, 2004, which isincorporated herein by reference. Representative compounds are offormula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)— or SO₂;

X is H;

Z is (C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)-OH,(C₁₋₄-alkyl)-O(C₁₋₄-alkyl), (C₁₋₄-alkyl)-SO₂(C₁₋₄-alkyl),(C₀₋₄-alkyl)-SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)-NH₂,(C₀₋₄-alkyl)-N(C₁₋₈alkyl)₂, (C₀₋₄-alkyl)-N(H)(OH), orCH₂NSO₂(C₁₋₄-alkyl);

R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or(C₁₋₄-alkyl)cycloalkyl;

R³ is, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);

R⁴ is H;

R⁵ is —OH, or —OC(O)R⁶;

R⁶ is C₁₋₈-alkyl, amino-(C₁₋₈-alkyl), (C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl),C₃₋₆-cycloalkyl, phenyl, benzyl, or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof; or formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)—, or SO₂;

X is halogen, —CN, —NR₇R₈, —NO₂, or —CF₃;

Z is (C₀₋₄alkyl)-SO₂(C₁₋₄-alkyl), —(C₀₋₄-alkyl)-CN,—(C₀₋₄-alkyl)-C(O)R³, C₁₋₄-alkyl, (C₀₋₄-alkyl)OH,(C₀₋₄-alkyl)O(C₁₋₄-alkyl), (C₀₋₄-alkyl)SO(C₁₋₄-alkyl), (C₀₋₄-alkyl)NH₂,(C₀₋₄-alkyl)N(C₁₋₈-alkyl)₂, (C₀₋₄-alkyl)N(H)(OH),(C₀₋₄-alkyl)-dichloropyridine or (C₀₋₄-alkyl)NSO₂(C₁₋₄-alkyl);

W is —C₃₋₆-cycloalkyl, —(C₁₋₈-alkyl)-(C₃₋₆-cycloalkyl),—(C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl)-NR₇R₈, (C₀₋₈-alkyl)-NR₇R₈,(C₀₋₄alkyl)-CHR₉—(C₀₋₄alkyl)-NR₇R₈;

R₁ and R₂ are independently C₁₋₈-alkyl, cycloalkyl, or(C₁₋₄-alkyl)cycloalkyl;

R³ is C₁₋₈-alkyl, NR⁴R⁵, OH, or O—(C₁₋₈-alkyl);

R⁴ and R⁵ are independently H, C₁₋₈-alkyl,(C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), OH, or —OC(O)R⁶;

R⁶ is C₁₋₈-alkyl, (C₀₋₈-allyl)-(C₃₋₆-cycloalkyl), amino-(C₁₋₈-alkyl),phenyl, benzyl, or aryl;

R₇ and R₈ are each independently H, C₁₋₈-alkyl,(C₀₋₈-alkyl)-(C₃₋₆-cycloalkyl), phenyl, benzyl, aryl, or can be takentogether with the atom connecting them to form a 3 to 7 memberedheterocycloalkyl or heteroaryl ring;

R₉ is C₁₋₄ alkyl, (C₀₋₄alkyl)aryl, (C₀₋₄alkyl)-(C₃₋₆-cycloalkyl),(C₀₋₄alkyl)-heterocycle; or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof. In anotherembodiment, W is

In another embodiment, representative compounds are of formula:

wherein:

R₁, R₂ and R₃ are independently H or C₁₋₈-alkyl, with the proviso thatat least one of R₁, R₂ and R₃ is not H;

and pharmaceutically acceptable salts, solvates, hydrates,stereoisomers, clathrates, or prodrugs thereof.

Still specific selective cytokine inhibitory drugs include, but are notlimited to, N-alkyl-hydroxamic acid-isoindolyl compounds disclosed inU.S. provisional application No. 60/454,149 filed on Mar. 12, 2003, andits U.S. non-provisional application entitled “N-alkyl-hydroxamicacid-isoindolyl compounds and their pharmaceutical uses” which was filedon Mar. 12, 2004 by Man et al. and the U.S. Ser. No. is to bedetermined, each of which is incorporated herein by reference.Representative compounds are of formula:

wherein:

Y is —C(O)—, —CH₂, —CH₂C(O)— or SO₂;

R₁ and R₂ are independently C₁₋₈-alkyl, CF₂H, CF₃, CH₂CHF₂, cycloalkyl,or (C₁₋₈-alkyl)cycloalkyl;

Z₁ is H, C₁₋₆-alkyl, —NH₂—NR₃R₄ or OR₅;

Z₂ is H or C(O)R₅;

X₁, X₂, X₃ and X₄ are each independent H, halogen, NO₂, OR₃, CF₃,C₁₋₆-alkyl, (C₀₋₄ alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₄-alkyl)-N—(R₈R₉),(C₀₋₄-alkyl)-NHC(O)—(R₈), (C₀₋₄-alkyl)-NHC(O)CH(R₈)(R₉),(C₀₋₄-alkyl)-NHC(O)N(R₈R₉), (C₀₋₄-alkyl)-NHC(O)O(R₈), (C₀₋₄-alkyl)-O—R₈,(C₀₋₄-alkyl)-imidazolyl, (C₀₋₄-alkyl)-pyrrolyl, (C₀₋₄-alkyl)oxadiazolyl, (C₀₋₄-alkyl)-triazolyl or (C₀₋₄-alkyl)-heterocycle;

R₃, R₄, and R₅ are each independently H, C₁₋₆-alkyl, O—C₁₋₆-alkyl,phenyl, benzyl, or aryl;

R₆ and R₇ are independently H or C₁₋₆-alkyl;

R₈ and R₉ are each independently H, C₁₋₉-alkyl, C₃₋₆-cycloalkyl,(C₁₋₆-alkyl)-(C₃₋₆-cycloalkyl), (C₀₋₆-alkyl)-N(R₄R₅), (C₁₋₆-alkyl)-OR₅,phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrrolidinyl,morpholino, or C₃₋₇-heterocycloalkyl; and

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof.

Still specific selective cytokine inhibitory drugs include, but are notlimited to, diphenylethylene compounds disclosed in U.S. patentapplication Ser. No. 10/794,931, filed on Mar. 5, 2004, which isincorporated herein by reference. Representative compounds are offormula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

wherein:

R₁ is —CN, lower alkyl, —COOH, —C(O)—N(R₉)₂, —C(O)-lower alkyl,—C(O)-benzyl, —C(O)O-lower alkyl, —C(O)O-benzyl;

R₄ is —H, —NO₂, cyano, substituted or unsubstituted lower alkyl,substituted or unsubstituted alkoxy, halogen, —OH, —C(O)(R₁₀)₂, —COOH,—NH₂, —OC(O)—N(R₁₀)₂;

R₅ is substituted or unsubstituted lower alkyl, substituted orunsubstituted alkoxy, or substituted or unsubstituted alkenyl;

X is substituted or unsubstituted phenyl, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrrolidine, substituted orunsubstituted imidizole, substituted or unsubstituted naphthalene,substituted or unsubstituted thiophene, or substituted or unsubstitutedcycloalkyl;

each occurrence of R₉ is independently —H or substituted orunsubstituted lower alkyl; and

each occurrence of R₁₀ is independently —H or substituted orunsubstituted lower alkyl. In another embodiment, representativecompounds are of formula:

and pharmaceutically acceptable salts, solvates or hydrates thereof,

wherein:

R₁ and R₂ are independently —H, —CN, substituted or unsubstituted loweralkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, —COOH, —C(O)-lower alkyl, —C(O)O-lower alkyl,—C(O)—N(R₉)₂, substituted or unsubstituted aryl, or substituted orunsubstituted heterocycle;

each occurrence of R_(a), R_(b), R_(c) and R_(d) is independently —H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen,cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀, —OC(O)—R₁₀—N(R₁₀)₂,—C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀, —NHC(O)NH—R₁₀,—NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;

R₃ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₃ with either R_(a) orwith R₄, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;

R₄ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;

R₅ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;

R₆ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;

R₇ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂;

R₈ is —H, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocycle,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkoxy, halogen, cyano, —NO₂, —OH, —OPO(OH)₂, —N(R₉)₂, —OC(O)—R₁₀,—OC(O)—R₁₀—N(R₁₀)₂, —C(O)N(R₁₀)₂, —NHC(O)—R₁₀, —NHS(O)₂—R₁₀, —S(O)₂—R₁₀,—NHC(O)NH—R₁₀, —NHC(O)N(R₁₀)₂, —NHC(O)NHSO₂—R₁₀, —NHC(O)—R₁₀—N(R₁₀)₂,—NHC(O)CH(R₁₀)(N(R₉)₂) or —NHC(O)—R₁₀—NH₂, or R₈ with either R_(c) orwith R₇, together form —O—C(R₁₆R₁₇)—O— or —O—(C(R₁₆R₁₇))₂—O—;

each occurrence of R₉ is independently —H, substituted or unsubstitutedlower alkyl, or substituted or unsubstituted cycloalkyl;

each occurrence of R₁₀ is independently substituted or unsubstitutedlower alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, orR₁₀ and a nitrogen to which it is attached form a substituted orunsubstituted heterocycle, or R₁₀ is —H where appropriate; and

each occurrence of R₁₆ and R₁₇ is independently —H or halogen.

Compounds of the invention can either be commercially purchased orprepared according to the methods described in the patents or patentpublications disclosed herein. Further, optically pure compositions canbe asymmetrically synthesized or resolved using known resolving agentsor chiral columns as well as other standard synthetic organic chemistrytechniques.

As used herein and unless otherwise indicated, the term“pharmaceutically acceptable salt” encompasses non-toxic acid and baseaddition salts of the compound to which the term refers. Acceptablenon-toxic acid addition salts include those derived from organic andinorganic acids or bases known in the art, which include, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinicacid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid,salicylic acid, phthalic acid, embolic acid, enanthic acid, and thelike.

Compounds that are acidic in nature are capable of forming salts withvarious pharmaceutically acceptable bases. The bases that can be used toprepare pharmaceutically acceptable base addition salts of such acidiccompounds are those that form non-toxic base addition salts, i.e., saltscontaining pharmacologically acceptable cations such as, but not limitedto, alkali metal or alkaline earth metal salts and the calcium,magnesium, sodium or potassium salts in particular. Suitable organicbases include, but are not limited to, N,N-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine(N-methylglucamine), lysine, and procaine.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,derivatives of selective cytokine inhibitory drugs that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Otherexamples of prodrugs include derivatives of a selective cytokineinhibitory drug that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in 1 Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elsevier, New York 1985).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzablecarbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,” and“biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate,ureide, or phosphate, respectively, of a compound that either: 1) doesnot interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl,acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, andpivaloyloxyethyl esters), lactonyl esters (such as phthalidyl andthiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such asmethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andisopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters,and acylamino alkyl esters (such as acetamidomethyl esters). Examples ofbiohydrolyzable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamatesinclude, but are not limited to, lower alkylamines, substitutedethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic andheteroaromatic amines, and polyether amines.

Various selective cytokine inhibitory drugs contain one or more chiralcenters, and can exist as racemic mixtures of enantiomers or mixtures ofdiastereomers. This invention encompasses the use of stereomericallypure forms of such compounds, as well as the use of mixtures of thoseforms. For example, mixtures comprising equal or unequal amounts of theenantiomers of selective cytokine inhibitory drugs may be used inmethods and compositions of the invention. The purified (R) or (S)enantiomers of the specific compounds disclosed herein may be usedsubstantially free of its other enantiomer.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, morepreferably greater than about 90% by weight of one stereoisomer of thecompound and less than about 10% by weight of the other stereoisomers ofthe compound, even more preferably greater than about 95% by weight ofone stereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 60% byweight of one stereoisomer of a compound, preferably greater than about70% by weight, more preferably greater than about 80% by weight of onestereoisomer of a compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4.2 Second Active Ingredients

One or more second active ingredients can be used in combination with aselective cytokine inhibitory drug of the present invention. Preferably,the second active ingredient, or agent, is capable of suppressing theoverproduction of hematopoietic stem cells, or ameliorating one or moreof the symptoms of MPD.

Second active agents can be, but are not limited to, small molecules(e.g., synthetic inorganic, organometallic, or organic molecules), largemolecules, synthetic drugs, peptides, polypeptides, proteins, nucleicacids, antibodies and the like. Any agent that is known to be useful, orthat has been used or is currently being used for the prevention,treatment or amelioration of one or more symptoms of MPD can be used inthe combination with the present invention. Particular agents include,but are not limited to, anticancer agents (e.g., antimetabolites,antibiotics, alkylating agents, microtubule inhibitors, steroidhormones, DNA-repair enzyme inhibitors, kinase inhibitors, farnesyltransferase inhibitors, antisense oligonucleotides, immunomodulators,antibodies, vaccines, and adnosine deaminase inhibitors), all-transretinoic acid (e.g., arsenic trioxide), platelet inhibitors (e.g.,aspirin, dipyridamole, ticlopidine, anagrelide), anticoagulants (e.g.,enoxaprin, heparin, warfarin), thrombolytic agents (e.g., alteplase(tPA), anistreplase, streptokinase, urokinase), antifibrosis agents(e.g., penicillamine, suramin, clochicine), agents used in treatingbleeding (e.g., aminocaproic acid, protamine sulfate, vitamin K), andagents used in treating anemia (e.g., vitamin K, folic acid).

This invention also encompasses the use of native, naturally occurring,and recombinant proteins. The invention further encompasses mutants andderivatives (e.g., modified forms) of naturally occurring proteins thatexhibit, in vivo, at least some of the pharmacological activity of theproteins upon which they are based. Examples of mutants include, but arenot limited to, proteins that have one or more amino acid residues thatdiffer from the corresponding residues in the naturally occurring formsof the proteins. Also encompassed by the term “mutants” are proteinsthat lack carbohydrate moieties normally present in their naturallyoccurring forms (e.g., nonglycosylated forms). Examples of derivativesinclude, but are not limited to, pegylated derivatives and fusionproteins, such as proteins formed by fusing IgG1 or IgG3 to the proteinor active portion of the protein of interest. See, e.g., Penichet, M. L.and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

This invention further encompasses the use of immune cells ortransplantation of blood and marrow stem cells. For example, CMLpatients can be treated with infusion of donor white blood cells thatsuppress the growth of leukemia cells. Slavin et al., Transfus ApheresisSci 27(2):159-66 (2002).

Examples of anti-cancer drugs that can be used in the variousembodiments of the invention, including the methods, dosing regimens,cocktails, pharmaceutical compositions and dosage forms and kits of theinvention, include, but are not limited to: acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethan immunomodulatory compoundof the invention; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib(COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine;crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine;dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; dacarbazine; docetaxel;doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifenecitrate; dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;estramustine; estramustine phosphate sodium; etanidazole; etoposide;etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine;fenretinide; floxuridine; fludarabine phosphate; fluorouracil;fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabinehydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;ilmofosine; interleukin II (including recombinant interleukin II, orrIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1;interferon alfa-n3; interferon beta-I a; interferon gamma-I b;iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate;letrozole; leuprolide acetate; liarozole hydrochloride; lometrexolsodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine;mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; oblimersen; ormaplatin;oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycinsulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; riboprine; rogletan immunomodulatorycompound of the invention; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; animmunomodulatory compound of the invention azoacridones; imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;lytic peptides; maitansine; mannostatin A; marimastat; masoprocol;maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;menogaril; merbarone; meterelin; methioninase; metoclopramide; MIFinhibitor; mifepristone; miltefosine; mirimostim; mismatched doublestranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide;mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;molgramostim; monoclonal antibody, human chorionic gonadotrophin;monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multipledrug resistance gene inhibitor; multiple tumor suppressor 1-basedtherapy; mustard anticancer agent; mycaperoxide B; mycobacterial cellwall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;nartograstim; nedaplatin; nemorubicin; neridronic acid; neutralendopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxideantioxidant; nitrullyn; O⁶-benzylguanine; octreotide; okicenone;oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oralcytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin;paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine;palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin;pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; porfimer sodium; porfiromycin;prednisone; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rogletan immunomodulatory compound of theinvention; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl;safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; signal transductionmodulators; single chain antigen binding protein; sizofuran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosariinoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; totipotent stem cell factor; translation inhibitors;tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;tropisetron; turosteride; tyrosine kinase inhibitors; tyrphosfins; UBCinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer. Preferred anti-cancer drugs arethose that have been shown to have treatment benefit in a MPD patient,e.g., interferon-α, hydroxyurea, busulfan, anagrelide, daunorubicin,cincristine, corticosteroid hormones (e.g., prednisone, beclomethasone,cortisone, dexamethasone, fludrocortisone, hydrocortisone,methylprednisolone), kinase inhibitors, topoisomerase inhibitors,farnesyl transferase inhibitors, vaccines and antisense nucleotides.

Examples of kinase inhibitors include, but are not limited to, compoundST1571, imatinib mesylate (Kantaijian et al., Clin Cancer Res.8(7):2167-76 (2002)), and those compounds disclosed in U.S. Pat. Nos.6,245,759, 6,399,633, 6,383,790, 6,335,156, 6,271,242, 6,242,196,6,218,410, 6,218,372, 6,057,300, 6,034,053, 5,985,877, 5,958,769,5,925,376, 5,922,844, 5,911,995, 5,872,223, 5,863,904, 5,840,745,5,728,868, 5,648,239, 5,587,459, all of which are incorporated herein byreference. Preferred kinase inhibitors include, but are not limited to,those that directly target the BCR/ABL kinase or other kinases that areinvolved in the MPD pathophysiology, e.g., ST1571, and imatinibmesylate.

Examples of topoisomerase inhibitors include, but are not limited to,camptothecin; irinotecan; SN-38; topotecan; 9-aminocamptothecin; GG-211(GI 147211); DX-8951f; IST-622; rubitecan; pyrazoloacridine; XR-5000;saintopin; UCE6; UCE1022; TAN-1518A; TAN-1518B; KT6006; KT6528; ED-10;NB-506; ED-110; N13-506; and rebeccamycin; bulgarein; DNA minor groovebinders such as Hoescht dye 33342 and Hoechst dye 33258; nitidine;fagaronine; epiberberine; coralyne; beta-lapachone; BC-4-1; andpharmaceutically acceptable salts, solvates, clathrates, and prodrugsthereof. See, e.g., Rothenberg, M. L., Annals of Oncology 8:837-855(1997); and Moreau, P., et al., J. Med. Chem. 41:1631-1640 (1998).Examples of camptothecin derivatives that can be used in the methods andcompositions of this invention are disclosed by, for example, U.S. Pat.Nos. 6,043,367; 6,040,313; 5,932,588; 5,916,896; 5,889,017; 5,801,167;5,674,874; 5,658,920; 5,646,159; 5,633,260; 5,604,233; 5,597,829;5,552,154; 5,541,327; 5,525,731; 5,468,754; 5,447,936; 5,446,047;5,401,747; 5,391,745; 5,364,858; 5,340,817; 5,244,903; 5,227,380;5,225,404; 5,180,722; 5,122,606; 5,122,526; 5,106,742; 5,061,800;5,053,512; 5,049,668; 5,004,758; 4,981,968; 4,943,579; 4,939,255;4,894,456; and 4,604,463, each of which is incorporated herein byreference. Preferred topoisomerase inhibitors include, but are notlimited to, DX-8951f, irinotecan, SN-38, and pharmaceutically acceptablesalts, solvates, clathrates, and prodrugs thereof.

Examples of farnesyl transferase inhibitor include, but are not limitedto, R115777, BMS-214662, (for review, see Caponigro, Anticancer Drugs13(8):891-897 (2002)), and those disclosed by, for example, U.S. Pat.Nos. 6,458,935, 6,451,812, 6,440,974, 6,436,960, 6,432,959, 6,420,387,6,414,145, 6,410,541, 6,410,539, 6,403,581, 6,399,615, 6,387,905,6,372,747, 6,369,034, 6,362,188, 6,342,765, 6,342,487, 6,300,501,6,268,363, 6,265,422, 6,248,756, 6,239,140, 6,232,338, 6,228,865,6,228,856, 6,225,322, 6,218,406, 6,211,193, 6,187,786, 6,169,096,6,159,984, 6,143,766, 6,133,303, 6,127,366, 6,124,465, 6,124,295,6,103,723, 6,093,737, 6,090,948, 6,080,870, 6,077,853, 6,071,935,6,066,738, 6,063,930, 6,054,466, 6,051,582, 6,051,574, 6,040,305, all ofwhich are incorporated herein by reference.

In one embodiment of the present invention, the second active agent isan agent used in the gene therapy of MPD. For example, antisenseoligonucleotides can block the encoding instructions of an oncogene sothat it cannot direct the formation of the corresponding oncoproteinthat causes the cell to transform into a malignant cell. Examples ofantisense oligonucleotides include, but are not limited to, thosedisclosed in the U.S. Pat. Nos. 6,277,832, 5,998,596, 5,885,834,5,734,033, and 5,618,709, all of which are incorporated herein byreference.

In another embodiment of the present invention, the second active agentis a protein, a fusion protein thereof, or a vaccine that secretes theprotein, wherein the protein is IL-2, IL-10, IL-12, IL18, G-CSF, GM-CSF,EPO, or a pharmacologically active mutant or derivative thereof. In somecircumstances apparent to one skilled in the art, G-CSF, GM-CSF and EPOare not preferred. For example, G-CSF, GM-CSF and EPO preferably are notused in methods that do not utilize stem cell transplantation. In apreferred embodiment, the protein is an antibody or an antibody linkedto a chemical toxin or radioactive isotope that targets and killsspecific overproduced cells in a MPD patient. Such antibodies include,but are not limited to, rituximab (Rituxan), calicheamycin (Mylotarg®,ibritumomab tiuxetan (Zevalin®), and tositumomab (Bexxar®).

In a specific embodiment of the present invention, the second activeagent is a vaccine that can induce antigen-specific anti-malignant cellimmune responses in a MPD patient. A non-limiting example of such avaccine is disclosed in U.S. Pat. No. 6,432,925, which is incorporatedherein by reference.

In yet another embodiment of the present invention, the second activeagent is one that is capable of reversal of multidrug resistance in MPDpatients. The overproduced cells in MPD patients have mechanisms thatmay allow them to escape the damaging effects of chemotherapy. Newagents are being studied to decrease resistance to an importantchemotherapeutic drug used in the treatment of leukemia. Non-limitingexamples of such agents are disclosed in U.S. Pat. No. 6,225,325, whichis incorporated herein by reference.

Other agents that can be used in combination with the present inventioninclude, but are not limited to those disclosed in U.S. Pat. Nos.6,096,300, 6,420,391, 6,326,205, 5,866,332, 6,458,349, 6,420,378,6,399,664, 6,395,771, 6,346,246, 6,333,309, 6,331,642, 6,329,497,6,326,378, 6,313,129, 6,306,393, 6,303,646, 6,265,427, 6,262,053,6,258,779, 6,251,882, 6,231,893, 6,225,323, 6,221,873, 6,218,412,6,204,364, 6,187,287, 6,183,988, 6,183,744, 6,172,112, 6,156,733,6,143,738, 6,127,406, 6,121,320, 6,107,520, 6,107,457, 6,075,015, and6,063,814, all of which are incorporated herein by reference.

4.3 Methods of Treatment and Management

Methods of this invention encompass methods of preventing, treatingand/or managing various types of MPD. As used herein, unless otherwisespecified, the terms “treating” and “preventing” encompass theinhibition or the reduction of the severity or magnitude of one or moresymptoms or laboratory findings associated with MPD. Symptoms associatedwith MPD include, but are not limited to, headache, dizziness, tinnitus,blurred vision, fatigue, night sweat, low-grade fever, generalizedpruritus, epistaxis, blurred vision, splenomegaly, abdominal fullness,thrombosis, increased bleeding, anemia, splenic infarction, severe bonepain, hematopoiesis in the liver, ascites, esophageal varices, liverfailure, respiratory distress, and priapism. Laboratory findingsassociated with MPD include, but are not limited to, clonal expansion ofa multipotent hematopoietic progenitor cell with the overproduction ofone or more of the formed elements of the blood (e.g., elevated redblood cell count, elevated white blood cell count, and/or elevatedplatelet count), presence of Philadelphia chromosome or bcr-abl gene,teardrop poikilocytosis on peripheral blood smear, leukoerythroblasticblood pictuer, giant abnormal platelets, hypercellular bone marrow withreticular or collagen fibrosis, and marked left-shifted myeloid serieswith a low percentage of promyelocytes and blasts. As used herein,unless otherwise specified, the term “treating” refers to theadministration of a composition after the onset of symptoms of MPD,whereas “preventing” refers to the administration prior to the onset ofsymptoms, particularly to patients at risk of MPD. As used herein andunless otherwise indicated, the term “managing” encompasses preventingthe recurrence of MPD in a patient who had suffered from MPD,lengthening the time a patient who had suffered from MPD remains inremission, and/or preventing the occurrence of MPD in patients at riskof suffering from MPD.

The invention encompasses methods of treating or preventing patientswith primary and secondary MPD. It further encompasses methods treatingpatients who have been previously treated for MPD, as well as those whohave not previously been treated for MPD. Because patients with MPD haveheterogenous clinical manifestations and varying clinical outcomes, ithas become apparent that staging the patients according to theirprognosis and approaching therapy depending on the severity and stagemay be necessary. Indeed, the methods and compositions of this inventioncan be used in various stages of treatments for patients with one ormore types of MPD including, but not limited to, polycythemia rubra vera(PRV), primary thromobocythemia (PT), chronic myelogenous leukemia(CML), and agnogenic myeloid metaplasia (AMM).

Methods encompassed by this invention comprise administering a selectivecytokine inhibitory drug of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrugthereof to a patient (e.g., a human) suffering, or likely to suffer,from MPD. Specific patient populations include the elderly, i.e., ages60 and above as well as those over 35 years of age. Patients withfamilial history of MPD or leukemia are also preferred candidates forpreventive regimens.

In one embodiment of the invention, the recommended daily dose range ofa selective cytokine inhibitory drug for the conditions described hereinlie within the range of from about 1 mg to about 10,000 mg per day,given as a single once-a-day dose, or preferably in divided dosesthroughout a day. More specifically, the daily dose is administeredtwice daily in equally divided doses. Specifically, a daily dose rangeshould be from about 1 mg to about 5,000 mg per day, more specifically,between about 10 mg and about 2,500 mg per day, between about 100 mg andabout 800 mg per day, between about 100 mg and about 1,200 mg per day,or between about 25 mg and about 2,500 mg per day. In managing thepatient, the therapy should be initiated at a lower dose, perhaps about1 mg to about 2,500 mg, and increased if necessary up to about 200 mg toabout 5,000 mg per day as either a single dose or divided doses,depending on the patient's global response. In a particular embodiment,3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidecan be preferably administered in an amount of about 400, 800, 1,200,2,500, 5,000 or 10,000 mg a day as two divided doses.

4.3.1 Combination Therapy with a Second Active Agent

Particular methods of the invention comprise administering 1) aselective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, and 2) a second active agent or activeingredient. Examples of selective cytokine inhibitory drugs of theinvention are disclosed herein (see, e.g., section 4.1); and examples ofthe second active agents are also disclosed herein (see, e.g., section4.2).

In particular embodiments, one or more selective cytokine inhibitorydrugs are administered in combination with the administration of one ormore therapies that are used to treat, manage, or preventmyeloproliferative diseases. A non-limiting example is the use ofselective cytokine inhibitory drugs of the invention in combination withthe administration of an anti-cancer cocktail regimen, such as, but notlimited to, a regimen that includes cytarabine and an anthracycline(e.g., daunorubicin or idarubicin).

Administration of the selective cytokine inhibitory drugs and the secondactive agents to a patient can occur simultaneously or sequentially bythe same or different routes of administration. The suitability of aparticular route of administration employed for a particular activeagent will depend on the active agent itself (e.g., whether it can beadministered orally without decomposing prior to entering the bloodstream) and the disease being treated. A preferred route ofadministration for a selective cytokine inhibitory drug is oral.Preferred routes of administration for the second active agents oringredients of the invention are known to those of ordinary skill in theart. See, e.g. Physicians' Desk Reference, 1755-1760 (56^(th) ed.,2002).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofMPD being treated or managed, the severity and stage of MPD, and theamount(s) of selective cytokine inhibitory drugs of the invention andany optional additional active agents concurrently administered to thepatient. In a particular embodiment, the second active agent isinterferon-α, hydroxyurea, anagrelide, arsenic troxide, ST1571, imatinibmesylate, DX-8951f, R115777, vincristine, daunorubicin, prednisone or acombination thereof. Interferon-α is administered in an amount of from 2to 5 million unites subcutaneously three times weekly. Hydroxyurea isadministered in an amount of from about 500 to about 1500 mg/d orally,adjusted to keep platelets less than 500,000/μL without reducing theneutrophil count to <2000/μL.

4.3.2 Use with Transplantation Therapy

In still another embodiment, this invention encompasses a method oftreating, preventing and/or managing MPD, which comprises administeringthe selective cytokine inhibitory drug of the invention, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug thereof, in conjunction with transplantationtherapy. As discussed elsewhere herein, the treatment of MPD is based onthe stages and mechanism of the disease. As inevitable leukemictransformation develops in certain stages of MPD, transplantation ofperipheral blood stem cells, hematopoietic stem cell preparation or bonemarrow may be necessary. The combined use of the selective cytokineinhibitory drug of the invention and transplantation therapy provides aunique and unexpected synergism. In particular, a selective cytokineinhibitory drug of the invention exhibits immunomodulatory activity thatmay provide additive or synergistic effects when given concurrently withtransplantation therapy in patients with MPD. A selective cytokineinhibitory drug of the invention can work in combination withtransplantation therapy reducing complications associated with theinvasive procedure of transplantation and risk of related Graft VersusHost Disease (GVHD). This invention encompasses a method of treating,preventing and/or managing MPD which comprises administering to apatient (e.g., a human) a selective cytokine inhibitory drug of theinvention, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof, before, during, or afterthe transplantation of umbilical cord blood, placental blood, peripheralblood stem cell, hematopoietic stem cell preparation or bone marrow.Examples of stem cells suitable for use in the methods of the inventionare disclosed in U.S. provisional patent application No. 60/372,348,filed Apr. 12, 2002 by R. Hariri et al., the entirety of which isincorporated herein by reference.

4.3.3 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents of theinvention are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest for a period of time, and repeating this sequentialadministration. Cycling therapy can reduce the development of resistanceto one or more of the therapies, avoid or reduce the side effects of oneof the therapies, and/or improves the efficacy of the treatment.

Consequently, in one specific embodiment of the invention, a selectivecytokine inhibitory drug of the invention is administered daily in asingle or divided doses in a four to six week cycle with a rest periodof about a week or two weeks. The invention further allows thefrequency, number, and length of dosing cycles to be increased. Thus,another specific embodiment of the invention encompasses theadministration of a selective cytokine inhibitory drug of the inventionfor more cycles than are typical when it is administered alone. In yetanother specific embodiment of the invention, a selective cytokineinhibitory drug of the invention is administered for a greater number ofcycles that would typically cause dose-limiting toxicity in a patient towhom a second active ingredient is not also being administered.

In one embodiment, a selective cytokine inhibitory drug of the inventionis administered daily and continuously for three or four weeks at a doseof from about 0.1 to about 150 mg/d followed by a break of one or twoweeks.

In one embodiment of the invention a selective cytokine inhibitory drugof the invention and a second active ingredient are administered orally,with administration of a selective cytokine inhibitory drug of theinvention occurring 30 to 60 minutes prior to a second activeingredient, during a cycle of four to six weeks. In another embodimentof the invention, the combination of a selective cytokine inhibitorydrug of the invention and a second active ingredient is administered byintravenous infusion over about 90 minutes every cycle. Typically, thenumber of cycles during which the combinatorial treatment isadministered to a patient will be from about one to about 24 cycles,more typically from about two to about 16 cycles, and even moretypically from about four to about eight cycles.

4.4 Pharmaceutical Compositions and Single Unit Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms of the invention comprise a selective cytokine inhibitorydrug, or a pharmaceutically acceptable salt, solvate, hydrate,stereoisomer, clathrate, or prodrug thereof. Pharmaceutical compositionsand dosage forms of the invention can further comprise one or moreexcipients.

Pharmaceutical compositions and dosage forms of the invention can alsocomprise one or more additional active ingredients. Consequently,pharmaceutical compositions and dosage forms of the invention comprisethe active ingredients disclosed herein (e.g., a selective cytokineinhibitory drug, or a pharmaceutically acceptable salt, solvate,hydrate, stereoisomer, clathrate, or prodrug thereof, and a secondactive ingredient). Examples of optional additional active ingredientsare disclosed herein (see, e.g. section 4.2).

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), or parenteral(e.g., subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), transdermal or transcutaneous administration to apatent. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease may contain larger amounts of one ormore of the active ingredients it comprises than a dosage form used inthe chronic treatment of the same disease. Similarly, a parenteraldosage form may contain smaller amounts of one or more of the activeingredients it comprises than an oral dosage form used to treat the samedisease. These and other ways in which specific dosage forms encompassedby this invention will vary from one another will be readily apparent tothose skilled in the art. See, e.g., Remington's PharmaceuticalSciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients may be accelerated by some excipients such as lactose, orwhen exposed to water. Active ingredients that comprise primary orsecondary amines are particularly susceptible to such accelerateddecomposition. Consequently, this invention encompasses pharmaceuticalcompositions and dosage forms that contain little, if any, lactose othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients thatare well known in the art and are listed, for example, in the U.S.Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositionscomprise active ingredients, a binder/filler, and a lubricant inpharmaceutically compatible and pharmaceutically acceptable amounts.Preferred lactose-free dosage forms comprise active ingredients,microcrystalline cellulose, pre-gelatinized starch, and magnesiumstearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention comprise aselective cytokine inhibitory drug, or a pharmaceutically acceptablesalt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof inan amount of from about 1 to about 1,200 mg. Typical dosage formscomprise a selective cytokine inhibitory drug, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereo isomer, clathrate, or prodrugthereof in an amount of about 1, 2, 5, 10, 25, 50, 100, 200, 400, 800,1,200, 2,500, 5,000 or 10,000 mg. In a particular embodiment, apreferred dosage form comprises3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidein an amount of about 400, 800 or 1,200 mg. Typical dosage formscomprise the second active ingredient in an amount of 1 to about 1000mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or fromabout 50 to about 200 mg. Of course, the specific amount of the secondactive ingredient will depend on the specific agent used, the type ofMPD being treated or managed, and the amount(s) of selective cytokineinhibitory drugs and any optional additional active agents concurrentlyadministered to the patient.

4.4.1 Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives; and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g. Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g. granules or powder), microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, pre-gelatinized starch, and mixtures thereof. The binder orfiller in pharmaceutical compositions of the invention is typicallypresent in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

A preferred solid oral dosage form of the invention comprises aselective cytokine inhibitory drug, anhydrous lactose, microcrystallinecellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydroussilica, and gelatin.

4.4.2 Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention. For example, cyclodextrin andits derivatives can be used to increase the solubility of a selectivecytokine inhibitory drug and its derivatives. See, e.g. U.S. Pat. No.5,134,127, which is incorporated herein by reference.

4.4.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms of the invention include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, orother forms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18^(th) eds., Mack Publishing, EastonPa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedby this invention are well known to those skilled in the pharmaceuticalarts, and depend on the particular tissue to which a givenpharmaceutical composition or dosage form will be applied. With thatfact in mind, typical excipients include, but are not limited to, water,acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,isopropyl myristate, isopropyl palmitate, mineral oil, and mixturesthereof to form solutions, emulsions or gels, which are non-toxic andpharmaceutically acceptable. Moisturizers or humectants can also beadded to pharmaceutical compositions and dosage forms if desired.Examples of such additional ingredients are well known in the art. See,e.g., Remington's Pharmaceutical Sciences, 16^(th) and 18^(th) eds.,Mack Publishing, Easton Pa. (1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.4.5 Kits

Typically, active ingredients of the invention are preferably notadministered to a patient at the same time or by the same route ofadministration. This invention therefore encompasses kits which, whenused by the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a patient.

A typical kit of the invention comprises a dosage form of a selectivecytokine inhibitory drug, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. Kitsencompassed by this invention can further comprise additional activeingredients such as, but not limited to, interferon-α, hydroxyurea,anagrelide, arsenic troxide, ST1571, imatinib mesylate, DX-8951f,R115777, vincristine, daunorubicin, prednisone, or a pharmacologicallyactive mutant or derivative thereof, or a combination thereof. Examplesof the additional active ingredients include, but are not limited to,those disclosed herein (see, e.g., section 4.2).

Kits of the invention can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits of the invention can further comprise cells or blood fortransplantation as well as pharmaceutically acceptable vehicles that canbe used to administer one or more active ingredients. For example, if anactive ingredient is provided in a solid form that must be reconstitutedfor parenteral administration, the kit can comprise a sealed containerof a suitable vehicle in which the active ingredient can be dissolved toform a particulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. EXAMPLES

The following studies are intended to further illustrate the inventionwithout limiting its scope.

5.1 Pharmacology and Toxicology Studies

A series of non-clinical pharmacology and toxicology studies areperformed to support the clinical evaluation of selective cytokineinhibitory drugs in human subjects. These studies are performed inaccordance with internationally recognized guidelines for study designand in compliance with the requirements of Good Laboratory Practice(GLP), unless otherwise noted.

The pharmacological properties of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide,including activity comparisons with thalidomide, are characterized in invitro studies. Studies examine the effects of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideon the production of various cytokines. In addition, a safetypharmacology study of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis conducted in dogs and the effects of the compound on ECG parametersare examined further as part of three repeat-dose toxicity studies inprimates.

5.2 Modulation of Cytokine Production

Inhibition of TNF-α production following LPS-stimulation of human PBMCand human whole blood by3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideis investigated in vitro (Muller et al., Bioorg. Med. Chem. Lett.9:1625-1630, 1999). The IC₅₀'s of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamidefor inhibiting production of TNF-α following LPS-stimulation of PBMC andhuman whole blood is measured.

5.3 Toxicology Studies

The effects of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideon cardiovascular and respiratory function are investigated inanesthetized dogs. Two groups of Beagle dogs (2/sex/group) are used. Onegroup receives three doses of vehicle only and the other receives threeascending doses of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide(400, 800, and 1,200 mg/kg/day). In all cases, doses of3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideor vehicle are successively administered via infusion through thejugular vein separated by intervals of at least 30 minutes.

The cardiovascular and respiratory changes induced by3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideare minimal at all doses when compared to the vehicle control group.

All patents cited herein are incorporated by reference in theirentireties. Embodiments of the invention described herein are only asampling of the scope of the invention. The full scope of the inventionis better understood with reference to the attached claims.

1-74. (canceled)
 75. A method of treating myeloproliferative disease,which comprises administering to a patient in need thereof atherapeutically effective amount of(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione,or a pharmaceutically acceptable salt or solvate thereof.
 76. A methodof claim 75, further comprising administering a therapeuticallyeffective amount of at least one second active agent.
 77. The method ofclaim 76, wherein the second active ingredient is capable of suppressingoverproduction of hematopoietic stem cells or ameliorating one or moreof the symptoms of the myeloproliferative disease.
 78. The method ofclaim 76, wherein the second active ingredient is a cytokine,corticosteroid, ribonucleotide reductase inhibitor, platelet inhibitor,anticoagulant, thrombolytic agent, antifibrosis agent, all-transretinoic acid, kinase inhibitor, topoisomerase inhibitor, farnesyltransferase inhibitor, antisense oligonucleotide, antibody, agent usedto reverse multidrug resistance, vaccine, myelosuppressive agent oranti-cancer agent.
 79. The method of claim 76, wherein the second activeingredient is interferon-α, hydroxyurea, anagrelide, busulfan, arsenictrioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine,daunorubicin, prednisone, or a pharmacologically active mutant orderivative thereof, or a combination thereof.
 80. A method of claim 75,wherein the myeloproliferative disease is polycythemia rubra vera (PRV),polycythemia vera, primary thromobocythemia (PT), chronic myelogenousleukemia (CML), or agnogenic myeloid metaplasia (AMM).
 81. A method ofclaim 75, wherein the compound is S enantiomer.
 82. A method of claim75, wherein the compound is administered before, during or aftertransplanting umbilical cord blood, placental blood, peripheral bloodstem cell, hematopoietic stem cell preparation or bone marrow into thepatient.